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Bibliography on: Alzheimer Disease — Treatment

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 01 Apr 2025 at 01:37 Created: 

Alzheimer Disease — Treatment

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: ( alzheimer*[TIAB] AND treatment[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2025-03-31

Liu X, Zhou B, Chen Y, et al (2025)

Design and synthesis of 2-phenyl-1H-benzo[d]imidazole derivatives as 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.

RSC medicinal chemistry pii:d4md00861h [Epub ahead of print].

It has been reported that 17β-HSD10 plays a key role in Alzheimer's disease. Here, a total of 44 2-phenyl-1H-benzo[d]imidazole derivatives were designed and synthesized as novel 17β-HSD10 inhibitors based on rational design and SAR studies. Among them, compound 33 (N-(4-(1,4,6-trimethyl-1H-benzo[d] imidazol-2-yl)phenyl)cyclohexanecarboxamide) showed high inhibitory efficacy (17β-HSD10 IC50 = 1.65 ± 0.55 μM) and low toxicity (HepaRG IC50 >100 μM). The Morris water maze experiment revealed that compound 33 could alleviate cognitive impairment induced by scopolamine in mice. This study facilitates the further development of more potent 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.

RevDate: 2025-03-31

Hoang MT, Zenker A, Saha S, et al (2025)

Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review.

HRB open research, 8:11.

INTRODUCTION: Dementia remains incurable, and treatment trials are typically conducted after the symptoms manifest, potentially too late in the disease process to alter its course. Early identification and intervention during the pre-diagnosis phase offer the potential to introduce more cost-effective strategies and enhance quality of life. This review aims to scrutinise emerging evidence and present a comprehensive summary of cost-effectiveness estimates of all strategies targeting the pre-diagnosis dementia population.

METHOD AND ANALYSIS: A systematic search will be conducted across six electronic databases. All articles will be assessed against pre-defined eligibility criteria through title and abstract screening, and full-text screening phases. Data from the included articles will be extracted using a standardized template. A newly established framework based on the CHEERS 2022 checklist will be applied to assess the reporting quality of the included articles. The entire review process, from screening to data extraction and quality assessment, will be a dual process conducted by two reviewers. Disagreements will be resolved by a third senior reviewer. The extracted data will be synthesised and presented in tables and figures.

CONCLUSION: This systematic review will present evidence of cost-effectiveness, along with the strengths and limitations of the existing literature. These findings aim to identify existing gaps, thereby informing and guiding the design of future studies in this domain.

ETHICS AND DISSEMINATION: Since this is a systematic review protocol, ethical approval is not required. The results will be published in a peer-reviewed journal, with both raw and summarised data shared through the journal or other open platforms.

PROSPERO - CRD42024521521.

RevDate: 2025-03-31

Cordeiro GA, Faria JA, Pavan L, et al (2025)

Evaluation of the neuroprotective potential of benzylidene digoxin 15 against oxidative stress in a neuroinflammation models induced by lipopolysaccharide and on neuronal differentiation of hippocampal neural precursor cells.

Frontiers in pharmacology, 16:1537720 pii:1537720.

Neuroinflammation, often driven by the overproduction of reactive oxygen species (ROS), plays a crucial role in the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The susceptibility of the brain to oxidative stress is attributed to its high metabolic activity and limited antioxidant defense. This study aimed to evaluate the neuroprotective potential of Benzylidene Digoxin 15 (BD-15) following treatment and pretreatment in a lipopolysaccharide (LPS)-induced neuroinflammation model. Additionally, we examined whether BD-15 enhances the generation of neurons from neural progenitor cells (NPCs).Male Wistar rats were used for acute treatment studies and divided into four groups: control (saline), BD-15 (100 μg/kg), LPS (250 μg/kg), and LPS + BD-15 (250 μg/kg + 100 μg/kg). Swiss albino mice were used for chronic pretreatment studies and divided into the following groups: control (saline), BD-15 (0.56 mg/kg), LPS (1 mg/kg), and LPS + BD-15 (1 mg/kg + 0.56 mg/kg). Behavioral changes were assessed using the open field test, and brain tissues were analyzed for oxidative stress markers, including malondialdehyde (MDA), reduced glutathione (GSH), protein carbonylation, catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST). To assess neurogenesis, primary NPC cultures derived from the hippocampus of newborn Wistar rats were used, which led to reduced locomotor activity and increased oxidative stress, particularly in the cortex, as indicated by elevated MDA levels and reduced GSH levels. BD-15 treatment reversed these effects, notably by restoring GSH levels and reducing protein carbonylation in the cerebellum. Chronic BD-15 treatment in Swiss mice improved oxidative stress markers including MDA, SOD, CAT, and GST. Furthermore, BD-15 exhibits neuroprotective properties by alleviating oxidative stress and motor dysfunction, suggesting its potential as a therapeutic agent for neuroinflammatory disorders. However, BD-15 did not affect NPC cell proliferation, indicating that this cardiotonic steroid did not alter the cell cycle of these progenitor cells.

RevDate: 2025-03-31

Chen X, Lv Z, Xie G, et al (2025)

Unleashing the potential: 40 Hz multisensory stimulation therapy for cognitive impairment.

Journal of central nervous system disease, 17:11795735251328029 pii:10.1177_11795735251328029.

Cognitive impairment encompasses a spectrum of disorders marked by acquired deficits in cognitive function, potentially leading to diminished daily functioning and work capacity, often accompanied by psychiatric and behavioral disturbances. Alzheimer's disease (AD) and Post-stroke cognitive impairment (PSCI) are significant causes of cognitive decline. With the global population getting older, AD and PSCI are becoming major health concerns, underscoring the critical necessity for successful treatment options. In recent years, various non-invasive biophysical stimulation techniques, including ultrasound, light, electric, and magnetic stimulation, have been developed for the treatment of central nervous system diseases. Preliminary clinical studies have demonstrated the feasibility and safety of these techniques. This review discuss the impact of 40 Hz multisensory stimulation on cerebral function, behavioral outcomes, and disease progression in both animal models and individuals exhibiting cognitive deficits, such as AD and PSCI. Furthermore, it summarizes the potential neural pathways involved in this therapeutic modality by synthesizing evidence from a variety of studies within the field. Subsequently, it evaluates the existing constraints of this technique and underscores the potential advantages of 40 Hz multisensory stimulation therapy for individuals with cognitive deficits, with the goal of enhancing the management and care of AD and PSCI.

RevDate: 2025-03-31

Han X, Gong S, Gong J, et al (2025)

Structural and metabolic topological alterations associated with butylphthalide treatment in mild cognitive impairment: Data from a randomized, double-blind, placebo-controlled trial.

Psychiatry and clinical neurosciences [Epub ahead of print].

AIMS: Effective intervention for mild cognitive impairment (MCI) is key for preventing dementia. As a neuroprotective agent, butylphthalide has the potential to treat MCI due to Alzheimer disease (AD). However, the pharmacological mechanism of butylphthalide from the brain network perspective is not clear. Therefore, we aimed to investigate the multimodal brain network changes associated with butylphthalide treatment in MCI due to AD.

METHODS: A total of 270 patients with MCI due to AD received either butylphthalide or placebo at a ratio of 1:1 for 1 year. Effective treatment was defined as a decrease in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) > 2.5. Brain networks were constructed using T1-magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. A support vector machine was applied to develop predictive models.

RESULTS: Both treatment (drug vs. placebo)-time interactions and efficacy (effective vs. ineffective)-time interactions were detected on some overlapping structural network metrics. Simple effects analyses revealed a significantly increased global efficiency in the structural network under both treatment and effective treatment of butylphthalide. Among the overlapping metrics, an increased degree centrality of left paracentral lobule was significantly related to poorer cognitive improvement. The predictive model based on baseline multimodal network metrics exhibited high accuracy (88.93%) of predicting butylphthalide's efficacy.

CONCLUSION: Butylphthalide may restore abnormal organization in structural networks of patients with MCI due to AD, and baseline network metrics could be predictive markers for therapeutic efficacy of butylphthalide.

CLINICAL TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR1800018362, Registration Date: 2018-09-13).

RevDate: 2025-03-31

Lu J, Yu P, Wang Y, et al (2025)

Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer's Disease-Related Psychosis.

Journal of medicinal chemistry [Epub ahead of print].

The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HT2CR dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named 21b. 21b exhibits submicromolar potency on both TAAR1 and 5-HT2CR targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that 21b was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. 21b also alleviated cognitive deficits and psychoactive symptoms in Alzheimer's disease (AD) model mice. Four week repeated dosing of 21b is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound 21b warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.

RevDate: 2025-03-30

Wang MT, Hu ZC, Xiang Y, et al (2025)

Fingolimod ameliorates amyloid deposition and neurodegeneration in APP/PS1 mouse model of Alzheimer's disease.

The journal of prevention of Alzheimer's disease pii:S2274-5807(25)00075-5 [Epub ahead of print].

INTRODUCTION: The immune system plays a critical role in regulating amyloid-beta (Aβ) metabolism in Alzheimer's Disease (AD). Both T and B lymphocytes are involved in the pathogenesis of AD. The sphingosine-1-phosphate (S1P) receptor modulator fingolimod used in the treatment of multiple sclerosis, can promote lymphocyte homing, potentially reducing the infiltration of peripheral lymphocytes into the brain.

METHODS: In this study, 8-month-old APP/PS1 mice were orally administered fingolimod at a dose of 1 mg/kg/day or saline as a control for 2 months. After treatment, the mice were subjected to behavioral tests, pathological examinations, and biochemical analyses to evaluate behavioral deficits and AD-type pathologies.

RESULTS: Fingolimod inhibits the infiltration of peripheral lymphocytes into the brain and reduces neuroinflammation. Fingolimod enhances cognitive function and alleviates brain Aβ deposition. Additionally, fingolimod treatment mitigates other AD-related pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Proteomic analysis further confirms the therapeutic effects of fingolimod in AD, reflected by the downregulation of proteins involved in multiple AD-associated pathways.

DISCUSSION: This study illustrates that fingolimod effectively ameliorates multiple pathological features of AD, highlighting its potential as a promising therapeutic candidate for the disease.

RevDate: 2025-03-30

Kshirsagar S, Alvir RV, Pradeepkiran JA, et al (2025)

Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.

Mitochondrion pii:S1567-7249(25)00033-9 [Epub ahead of print].

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.

RevDate: 2025-03-30

Wang W, Liu Z, Cheng H, et al (2025)

Cerium-doped carbon dots as dual-target agents against Alzheimer's β-amyloid fibrillogenesis and reactive oxygen species.

Colloids and surfaces. B, Biointerfaces, 252:114655 pii:S0927-7765(25)00162-6 [Epub ahead of print].

Both fibrillogenesis of amyloid β-protein (Aβ) and elevated levels of reactive oxygen species (ROS) contribute to the pathogenesis of Alzheimer's disease (AD). Beyond Aβ aggregation inhibition, the complexity necessitates the development of comprehensive therapeutic interventions for halting AD progression. Herein, a dual-target agent capable of Aβ aggregation inhibition and ROS scavenging was synthesized by doping cerium into carbon dots (Ce CDs). Ce CDs with a high Ce (III)/Ce (IV) ratio of 0.67 can scavenge various ROS, including superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and Aβ40-induced ROS, thus mitigating cellular oxidative damage and rescuing cell viability. Additionally, Ce CDs present potent inhibition on Aβ40 on-pathway fibrillization, disrupting the formation of highly ordered β-sheet structures and increasing cell viability from 50.2 % to 91.9 %. It is validated that the electrostatic interactions between Ce CDs and Aβ40 are primarily responsible for preventing the conformational transition of Aβ40 monomers. In vivo experiments with the transgenic Caenorhabditis elegans strain further validate the bifunctionality of Ce CDs in suppression of Aβ fibrillogenesis and attenuation of oxidative stress, thereby demonstrating the potential of combination therapy for AD. This finding highlights the important role of electrostatic interactions between Aβ and inhibitors in regulating Aβ aggregation, and provides new insights into the development of multifunctional agents for AD treatment.

RevDate: 2025-03-29

Kshirsagar S, Reddy AP, PH Reddy (2025)

Beneficial effects of mitophagy enhancers on amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer's disease.

Mitochondrion pii:S1567-7249(25)00035-2 [Epub ahead of print].

The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Research spanning over two decades highlights the critical role of mitochondrial dysfunction and synaptic damage in the pathogenesis of both early-onset and late-onset AD. Emerging evidence suggests impaired clearance of damaged mitochondria is an early pathological event in AD, positioning mitophagy enhancers as potential therapeutic candidates. This study determined the optimal doses of four mitophagy enhancers-Urolithin A (UA), actinonin, tomatidine, and nicotinamide riboside (NR)-using immortalized mouse hippocampal (HT22) neurons. HT22 cells were transfected with mutant APP (mAPP) cDNA and treated with the enhancers. The effects were assessed by evaluating mRNA and protein expression levels of genes involved in mitochondrial dynamics, biogenesis, mitophagy, and synaptic function, alongside cell survival and mitochondrial respiration. Mitochondrial morphology was also examined in treated and untreated mAPP-HT22 cells. Results showed that mAPP-HT22 cells exhibited increased mitochondrial fission, reduced fusion, downregulated synaptic and mitophagy-related genes, diminished cell survival, impaired mitochondrial respiration, and excessively fragmented, shortened mitochondria. Treatment with mitophagy enhancers reversed these deficits, restoring mitochondrial and synaptic health. Enhanced cell survival, upregulation of mitochondrial fusion, synaptic, and mitophagy genes, improved mitochondrial structure, and reduced fragmentation were observed. Notably, UA demonstrated the most robust mitigating effects. These findings underscore the therapeutic potential of mitophagy enhancers, particularly UA, as promising candidates to treat mitochondrial and synaptic dysfunctions in AD.

RevDate: 2025-03-29
CmpDate: 2025-03-29

Odu P, Odu VK, Oyebanjo OT, et al (2024)

Cognitive And Neuroprotective Effects of Vernonia amygdalina in scopolamine-induced Memory impaired Rats.

Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria, 39(2):233-240.

Cognitive impairment is largely associated with functional and structural loss in the brain of Alzheimer's disease (AD) models, and scopolamine has been successfully used to mimic these deficits in rodents. The cost and side effects of drugs presently used for the treatment of AD-related cognitive impairment have prompted research into alternative products, especially natural ones with high antioxidant capacity, since oxidative stress is a major pathophysiology associated with AD. The current study evaluated the cognitive and neuroprotective effects of Vernonia amygdalina (VA) on scopolamine-induced cognitive impairment in rats. Thirty-five male rats, randomly divided into seven groups (n = 5), were used. Group 1 served as the control and received distilled water. Groups 2 and 3 received Vernonia amygdalina, VA (50 and 100 mg/kg, respectively) per orally (p.o.). Group 4 received 1 mg/kg scopolamine SC (i.p.). Groups 5, 6, and 7 received pretreatment with either VA 50 mg/kg, VA 100 mg/kg, or Donepezil, DP (1 mg/kg), and then in combination with SC (1 mg/kg). The animals were subjected to memory tasks using the Morris water maze (MWM) and novel object recognition tasks (NORT) and sacrificed on day 14, after which their brains were isolated for biochemical and histological studies. The study showed that during MWM and NORT, spatial and non-spatial recognition memories, which were respectively impaired in the SC group compared to the control group, were reversed in the VA pretreatment groups. Scopolamine injection caused significant decreases in superoxide dismutase and catalase levels and an increase in malonaldehyde (MDA) levels in group 4 compared with the control group. Pretreatments with either VA or DP, however, caused a significant increase in the SOD and catalase levels and a decrease in the MDA level compared with the SC group. Histological studies revealed that VA was more potent in protecting the brain against SC-induced neurodegeneration and morphological alterations in the hippocampus and prefrontal cortex. Findings of this study suggest that VA attenuates scopolamine-induced cognitive deficits via inhibition of oxidative stress and neuronal degeneration and enhancement of cognition in the brains of rats.

RevDate: 2025-03-29

Donaghy PC, Hasoon J, Hamilton CA, et al (2025)

Plasma Biomarkers and Disease Prognosis in Mild Cognitive Impairment with Lewy Bodies.

Movement disorders : official journal of the Movement Disorder Society [Epub ahead of print].

BACKGROUND: Little is known about the prognostic value of plasma biomarkers in mild cognitive impairment with Lewy bodies (MCI-LB).

OBJECTIVES: To investigate the association of four plasma biomarkers with disease progression in MCI.

METHODS: Plasma amyloid-beta (Aβ)42/40, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 181 (pTau181) were measured at baseline in a longitudinal MCI cohort (n = 131).

RESULTS: Baseline plasma NfL was associated with increased risk of dementia/death in the entire cohort. In MCI-LB, baseline plasma NfL, GFAP, and pTau181 were associated with increased risk of dementia/death and increased cognitive decline measured by the Addenbrooke's Cognitive Examination-Revised.

CONCLUSIONS: pTau181, GFAP, and NfL are associated with more rapid disease progression in MCI-LB and, with further validation, could be useful to support prognosis and stratification for clinical practice and treatment trials. Further work, including clinicopathological studies, is needed to understand the biological correlates of these markers in MCI-LB. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

RevDate: 2025-03-31
CmpDate: 2025-03-29

Jahng GH, Lee MB, OI Kwon (2025)

Gadolinium based contrast agent induced electrical conductivity heterogeneity analysis in the brain of Alzheimer's disease.

Scientific reports, 15(1):10832.

Magnetic resonance imaging (MRI) often uses gadolinium-based contrast agents (GBCAs) to improve the characterization of imaging contrast, owing to their strong paramagnetic properties. Magnetic resonance electrical properties tomography (MREPT) visualizes the conductivity distribution of biological tissues at the Larmor frequency using the [Formula: see text] field phase signal. In this paper, we investigate the effect of GBCA on brain conductivity. To compare the differences of reconstructed noisy conductivity maps before and after the GBCA injection, we propose a method to remove the background low-frequency noise artifact based on an elliptic partial differential equation. By analyzing the relationship between electrical conductivity and magnetic permeability, the objective of this study is to develop a cost-effective and accessible initial screening imaging tool for diagnosing and monitoring the treatment of Alzheimer's disease (AD) pathophysiology. To investigate vascular damage in AD, we define a conductivity heterogeneity volume fraction (CHVF) caused by GBCA leakage. Using CHVF, we develop three indices to characterize mild cognitive impairment (MCI) and AD. To verify the proposed method, we studied a total of 42 participants, including 14 individuals diagnosed with AD, 18 participants with MCI, and 10 cognitively normal (CN) participants. Finally, we designed a radar chart informed by the CHVF analysis, to exhibit the pertinent parameters for MCI and AD patients, facilitating the evaluation and ongoing monitoring of each patient's diagnosis and treatment regimen.

RevDate: 2025-03-28

Rabinovici GD, Selkoe DJ, Schindler SE, et al (2025)

Donanemab: Appropriate use recommendations.

The journal of prevention of Alzheimer's disease pii:S2274-5807(25)00094-9 [Epub ahead of print].

Donanemab (Kisunla®), an IgG1 monoclonal antibody targeting N-terminal pyroglutamate-modified forms of amyloid-β, is approved in the United States for treatment of early symptomatic Alzheimer's disease (AD). Appropriate Use Recommendations (AUR) were developed to guide the implementation of donanemab in real-world practice, prioritizing safety considerations and opportunity for effectiveness. The AUR were developed by the AD and Related Disorders Therapeutic Workgroup by consensus, integrating available data and expert opinion. Appropriate candidates for donanemab treatment include persons with mild cognitive impairment or mild dementia due to AD (Clinical Stages 3-4, MMSE 20-30) who have biomarker confirmation of AD pathology by PET or CSF. Tau PET is not required for eligibility. Apolipoprotein E (APOE) genotyping should be performed prior to treatment to inform an individual's risk of developing Amyloid-Related Imaging Abnormalities (ARIA). Pre-treatment MRI should be obtained no more than 12 months prior to treatment. Patients with findings of >4 cerebral microbleeds, cortical superficial siderosis or a major vascular contribution to cognitive impairment should be excluded from treatment. The decision to initiate therapy should be grounded in a shared decision-making process that emphasizes the patient's values and goals of care. Donanemab is administered as a monthly intravenous infusion. Surveillance MRIs to evaluate for ARIA should be performed prior to the 2nd, 3rd, 4th and 7th infusions, prior to the 12th dose in higher risk individuals, and at any time ARIA is suspected clinically. Clinicians may consider discontinuing treatment if amyloid clearance is demonstrated by amyloid PET, typically obtained 12-18 months after initiating treatment.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Chen Y, Cheng H, Tao H, et al (2025)

Dual-mode sensing platform based on an iodide ion synergistic covalent triazine frameworks (CTFs) for point-of-care testing (POCT) of acetylcholinesterase.

Analytica chimica acta, 1350:343836.

Acetylcholinesterase (AChE) plays a critical role in maintaining nervous system homeostasis and coordinating essential biological reactions. AChE is an important biomarker for early diagnosis and treatment, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Therefore, developing efficient and immediate sensing platforms for AChE detection is crucial for advancing early diagnostic tools. In this study, we developed a dual-mode colorimetric/photothermal sensing platform based on iodide ion-synergized covalent porphyrin-triazine backbone nanozymes (Zn-CTF/I) to detect AChE with high sensitivity and reliability. The synergistic interaction between iodide ions and zinc atoms effectively modulated the electronic structure of the catalytic active site, significantly enhancing the peroxidase-like (POD-like) activity of Zn-CTF/I. This enhancement led to a 10-fold reduction in the AChE detection limit compared to controls, with a minimum detection limit of 0.003 U L[-1], outperforming other reported assays. The integration of temperature-based photothermal signals with colorimetric detection improved the platform's accuracy and reliability. The system also demonstrated excellent recovery performance in detecting AChE in complex serum samples. The proposed dual-mode sensing platform provides a sensitive, reliable, and robust tool for AChE detection, with promising applications in early diagnosis and treatment monitoring of neurodegenerative diseases.

RevDate: 2025-03-28

Wang Y, Lei X, Zhao D, et al (2025)

Revealing the effective components and mechanism of Zhimu-Huangbai herb-pair in the treatment of Alzheimer's disease.

Journal of ethnopharmacology pii:S0378-8741(25)00383-6 [Epub ahead of print].

The Zhimu-Huangbai herb-pair (ZB) is one of the most widely accepted prescriptions for treating Alzheimer's disease (AD) in traditional Chinese medicine. However, the effective components and mechanism of ZB for treating AD have not been fully understood.

AIM OF THE STUDY: This study aims to reveal the active components of ZB in the treatment of AD through serum pharmacochemistry, identify the potential targets and pathways of ZB in treating AD through metabolomics, and subsequently verify its mechanism through in vivo experiments.

MATERIALS AND METHODS: The components of ZB in both blood and cerebrospinal fluid were determined by using UPLC-Q-TOF-MS. The efficacy of ZB was assessed in a mouse model of AD induced by D-galactose. Metabolomics methods were used for screening and identification of differential metabolites and enrichment analysis of metabolic pathways. The enzyme-linked immunosorbent assay (ELISA) was used to detect the activities of enzyme complexes I-IV, as well as the levels of ATP and ROS in hippocampal mitochondria of mice. Additionally, the expression of key genes and proteins in the signaling pathway was examined by utilizing immunohistochemistry, real-time quantitative PCR, and Western blot.

RESULTS: A total of 27 prototype components were identified from the serum of rats given ZB, of which 8 components were simultaneously detected in the cerebrospinal fluid. A total of 20 different metabolites were identified from mouse plasma using a metabolomics technique. The enrichment analysis results revealed that the pathway of ZB treatment for AD mainly involves glycerophospholipid metabolism, arachidonic acid metabolism, and unsaturated fatty acid biosynthesis. In vivo experiments have shown that ZB can improve the energy metabolism of the brain and increase the production of ATP by improving mitochondrial dysfunction. In addition, ZB could promote the release of brain-derived neurotrophic factor (BDNF), increase the density of postsynaptic density protein (PSD95), and enhance the expression of synaptophysin (SYN).

CONCLUSION: Our study demonstrates that ZB can improve mitochondrial and synaptic function in AD mice induced by D-gal, providing experimental support for the clinical application and drug development for the prevention and treatment of AD.

RevDate: 2025-03-28

Hida M, Yasuda K, Toyokawa M, et al (2025)

Amyloidogenic and non-amyloidogenic pathways of amyloid precursor protein processing in oligodendrocytes.

Brain research pii:S0006-8993(25)00160-X [Epub ahead of print].

Excessive accumulation of toxic amyloid-β (Aβ) species in the brain is a major pathological process triggering neurodegeneration in Alzheimer's disease (AD). Recent studies indicate that both neurons and glial cells, including oligodendrocyte lineages (OLs), contribute to brain homeostasis and affect AD pathology; however, the roles of oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLGs) in AD remain to be fully elucidated. This study examined Aβ production and related protein expression in primary cultured OLs. Primary cultured OLs produced Aβ40 and Aβ42 and expressed amyloid precursor protein (APP), β-secretase (BACE1) and γ-secretase (PS1) as well as α-secretase (ADAM10). OLGs express APP770 in addition to APP695. Treatment with a γ-secretase inhibitor reduced Aβ40 and Aβ42 production levels derived from OPCs/OLGs and suppressed OPC differentiation. Additionally, conditioned media from OLGs improved neuronal cell viability under oxidative stress and contained higher levels of sAPPα compared to OPCs. The neuroprotective effect of OLG was diminished by a sAPPα inhibitor, suggesting that OLG-derived sAPPα protects neurons under oxidative stress. These findings revealed that OLs produce pathogenic Aβ40/42 via the amyloidogenic pathway and secrete neuroprotective sAPPα via the non-amyloidogenic pathway. Elucidating the pathological shift from beneficial non-amyloidogenic to harmful amyloidogenic processes in OLs during AD onset and progression would provide crucial insights into novel therapeutic approaches.

RevDate: 2025-03-28

Costa ML, Casanova-Martinez D, Chen H, et al (2025)

Implications of the glymphatic system in the pathogenesis of normal pressure hydrocephalus: an illustrated scoping review.

Journal of neurosurgery [Epub ahead of print].

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the clinical triad of cognitive impairment, gait disturbances, and urinary incontinence, coupled with ventricular enlargement on brain imaging. The pathophysiology of iNPH remains complex, with varied patient responses to CSF diversion and a generally progressive nature of the disease. This scoping review aimed to provide an overview of the glymphatic system (GS) and its role in the development of iNPH. The review highlights the crucial function of the GS in maintaining brain homeostasis by clearing waste products from the interstitial space. Dysfunction in this system leads to impaired CSF clearance, resulting in the accumulation of neurotoxic substances that contribute to the symptoms of iNPH. Additionally, potential shared pathophysiological pathways between iNPH and other conditions affecting the GS such as aging, diabetes mellitus, hypertension, and sleep disorders are discussed. The findings suggest that GS dysfunction is a key factor in iNPH pathogenesis and may also be linked to the disease's poor responsiveness to shunt treatment. By enhancing understanding of these mechanisms, there is potential to develop targeted therapies aimed at restoring glymphatic function, thereby improving outcomes for patients with iNPH.

RevDate: 2025-03-28

Norata D, Capone F, Motolese F, et al (2025)

1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.

Aging and disease pii:AD.2024.0573 [Epub ahead of print].

Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.

RevDate: 2025-03-31
CmpDate: 2025-03-31

Loupy KM, Dawud LM, Zambrano CA, et al (2025)

Effects of Oral Administration of the Probiotic Lactobacillus rhamnosus GG on the Proteomic Profiles of Cerebrospinal Fluid and Immunoregulatory Signaling in the Hippocampus of Adult Male Rats.

Neuroimmunomodulation, 32(1):94-109.

INTRODUCTION: The microbiome-gut-brain axis, by modulating bidirectional immune, metabolic, and neural signaling pathways in the host, has emerged as a target for the prevention and treatment of psychiatric and neurological disorders. Oral administration of the probiotic bacterium Lactobacillus rhamnosus GG (LGG; ATCC 53103) exhibits anti-inflammatory effects, although the precise mechanisms by which LGG benefits host physiology and behavior are not known. The goal of this study was to explore the general effects of LGG on the cerebrospinal fluid (CSF) proteome and a biological signature of anti-inflammatory signaling in the central nervous system (CNS) of undisturbed, adult male rats.

METHODS: Liquid chromatography-tandem mass spectrometry-based proteomics were conducted using CSF samples collected after 21 days of oral treatment with live LGG (3.34 × 107 colony-forming units (CFU)/mL in the drinking water (resulting in an estimated delivery of ∼1.17 × 109 CFU/day/rat) or water vehicle. Gene enrichment analysis (using DAVID, v. 6.8) and protein-protein interactions (using STRING, v. 11) were used to explore physiological network changes in CSF. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was performed to assess gene expression changes of anti-inflammatory cytokines in the hippocampus. Genes associated with anti-inflammatory signaling that were analyzed included Il10, Tgfb1, Il4, and IL-4-responsive genes, Cd200, Cd200r1, and Mrc1 (Cd206).

RESULTS: Oral LGG administration altered the abundance of CSF proteins, increasing the abundance of five proteins (cochlin, NPTXR, reelin, Sez6l, and VPS13C) and decreasing the abundance of two proteins (CPQ, IGFBP-7) in the CSF. Simultaneously, LGG increased the expression of Il10 mRNA, encoding the anti-inflammatory cytokine interleukin 10, in the hippocampus.

CONCLUSION: Oral LGG altered the abundance of CSF proteins associated with extracellular scaffolding, synaptic plasticity, and glutamatergic signaling. These data are consistent with the hypothesis that oral administration of LGG improves memory and cognition, and promotes a physiological resilience to neurodegenerative disease, by increasing glutamatergic signaling and promoting an anti-inflammatory environment in the brain.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Dantas LP, Carneiro de Vasconcelos E, da Silva Cunha C, et al (2025)

Protective effects of alpha-lipoic acid on memory deficit induced by repeated doses of solifenacin in mice: the role of nitro-oxidative stress.

Metabolic brain disease, 40(4):165.

Solifenacin (Sol) is one of the most used antimuscarinics for the treatment of bladder dysfunction and there are no conclusive studies on its effects on learning and memory after long-term use. Since substances with antioxidant action, such as alpha-lipoic acid (ALA), have shown protective action in memory deficit and Alzheimer's disease, we decided to study the effects of Sol alone or associated with ALA in behavioral tests of memory and its relation to nitro-oxidative stress in different brain areas. Mice received saline or Sol p.o. for 14 or 28 days. ALA groups received: (a) saline + ALA, (b) Sol for 14 days and Sol + ALA from the 15th to the 28th days and, (c) Sol + ALA for 28 days. Behavioral tests were performed and oxidative changes (lipid peroxidation) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were also determined. Sol produced memory alterations in the mice, reducing the step-down latency and the recognition index in the novel object recognition test. Sol also increased lipid peroxidation in PFC, HC and ST and nitrite levels in the HC. On the other hand, ALA associated with Sol was able to restrict the effects caused by Sol alone, both in relation to nitro-oxidative parameters and in relation to behavioral tests. Taken together, our data suggest that ALA can be administered as an adjunctive drug in patients requiring prolonged use of Sol to mitigate these adverse central nervous system effects. However, clinical studies need to be performed to corroborate preclinical research.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Awad SM, Attia YA, ElSayed H, et al (2025)

Efficacy of curcumin-selenium nanoemulsion in alleviating oxidative damage induced by aluminum chloride in a rat model of Alzheimer's disease.

Journal of molecular histology, 56(2):122.

Alzheimer's disease (AD) is a common neurological disorder primarily affecting older adults. A hallmark of this condition is the generation of reactive oxygen species (ROS), leading to increased oxidative stress and cellular damage. Treatment with a curcumin-selenium nanoemulsion has been shown to enhance behavioural performance and mitigate degenerative changes induced by aluminium chloride (AlCl3). This nanoemulsion also reduced the activity of acetylcholinesterase (AChE) and lowered levels of key proteins, including Aβ, p53, tau, nuclear factor erythroid 2-related factor 2 (Nrf2), and tumour necrosis factor-alpha (TNF-α). Additionally, it significantly decreased nitric oxide (NO) levels in the brain while enhancing the activity of catalase (CAT) and superoxide dismutase (SOD). The study highlights the antioxidant and anti-inflammatory properties of the curcumin-selenium nanoemulsion, suggesting its potential as a therapeutic option for alleviating AD induced by AlCl3. These results are further supported by improvements in the histological structure of the cortex and hippocampus, as well as enhanced immunohistochmical assessment of glial fibrillary acidic protein (GFAP). Cur- Se-nanoemulsion, the current drug delivery technology, may lower the amount of amyloid-β in AD rat brain and considerably ameliorate the memory deficit that improve therapy efficacy in AD lesions.

RevDate: 2025-03-28

Issa EHB, Alghazo EM, Gharaibeh R, et al (2025)

Therapeutic potential and challenges of mesenchymal stem cells in neurological disorders: A concise analysis.

Journal of neuropathology and experimental neurology pii:8097959 [Epub ahead of print].

Neurological diseases comprise a wide array of conditions affecting both the central and peripheral nervous systems. Neurodegenerative diseases encompass a group of debilitating and often fatal neurological disorders for which effective treatments are currently lacking. Stem cells are recognized for their remarkable capacity for proliferation, multilineage differentiation, and self-renewal. The transplantation of stem cells represents a significant advancement in therapeutic strategies for neurological disorders, with applications in both preclinical and clinical settings. Mesenchymal stem cells (MSCs), in particular, have garnered substantial interest due to their unique properties, making them a highly sought-after source of therapeutic cells. Although the efficacy of MSCs in treating neurological disorders is well documented, further research is needed to elucidate the underlying mechanisms and to assess their in vivo applications more comprehensively. This article summarizes current research on the use of MSCs in the treatment of various neurological disorders, including Parkinson disease, stroke, multiple sclerosis, and Alzheimer disease.

RevDate: 2025-03-28

Yadav M, VP Singh (2025)

A review on benzoselenazoles: synthetic methodologies and potential biological applications.

Organic & biomolecular chemistry [Epub ahead of print].

Among the various heterocyclic organoselenium compounds, a new class of benzoselenazoles has received great attention due to their chemical properties and biological applications. The ever-growing interest in the five-membered benzoselenazole heterocycles amongst chemists has made commendable impact. These heterocycles are a prominent class of organic molecules that have emerged as potential therapeutic agents for the treatment of a wide range of diseases. Substantial progress has been made in elucidating the complex chemical properties of these heterocycles. Moreover, they have garnered significant importance in a wide range of biological applications. However, despite their biological activities, research on benzoselenazoles remains relatively limited, emphasising the need for further exploration in this area. Hence, considering the importance of benzoselenazoles, this comprehensive review compiles various synthetic procedures, highlighting the recent advances in their synthesis that have been disclosed in the literature. This review would offer chemists an array of information that will assist them in the development of more affordable and effective synthesis processes for benzoselenazoles. Therefore, it is believed that this review would provide relevant context on these achievements and will inspire synthetic organic chemists to use these effective technologies of such heterocycles for the future treatment of diseases caused by oxidative stress. The biological and pharmacological properties of these organoselenium heterocycles, which include their antioxidant, antitumor, and antibacterial activities and their application in Alzheimer's disease treatment and as pancreatic lipase inhibitors, are thoroughly summarized. Finally, this review provides some perspectives on the challenges and future directions in the development of benzoselenazoles as heterocyclic organoselenium compounds.

RevDate: 2025-03-28

Zhai Y, Lu K, Yuan Y, et al (2025)

Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.

RevDate: 2025-03-28

Bartolini E, Di Crosta A, La Malva P, et al (2025)

Gamma oscillation modulation for cognitive impairment: A systematic review.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundGamma oscillation modulation has emerged as a potential non-invasive treatment to counteract cognitive impairment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Non-invasive brain stimulation techniques like transcranial alternating current stimulation (tACS), gamma sensory stimulation (GSS), and transcranial magnetic stimulation (TMS) show promise in supporting specific cognitive functions.ObjectiveTo review and evaluate the efficacy of gamma oscillation modulation techniques in benefiting cognitive functions among individuals with AD and MCI.MethodsA systematic review was conducted, analyzing studies from 2015 to 2023 across databases such as PubMed, Web of Science, and Scopus. Inclusion criteria focused on studies involving tACS, GSS, or TMS applied to older adults with MCI or AD. A total of 438 articles were screened, of which 10 met the eligibility criteria.ResultsFindings suggest that gamma tACS, especially targeting the precuneus and dorsolateral prefrontal cortex, benefits episodic memory and cognitive performance. GSS also showed potential in supporting memory and attention, while TMS exhibited inconsistent but promising results when applied to the angular gyrus. However, heterogeneity in study designs and small sample sizes limit the generalizability of these outcomes.ConclusionsGamma oscillation modulation offers potential cognitive benefits for patients with AD and MCI, particularly in memory support. Further studies with larger samples and well-designed protocols are needed to confirm its therapeutic efficacy and optimize intervention parameters.

RevDate: 2025-03-28

Grant KL, SN Long (2025)

Extended release huperzine for the treatment of idiopathic epilepsy in dogs - a Case Report.

Frontiers in veterinary science, 12:1518379.

Huperzine is a naturally occurring alkaloid derived from the Chinese clubmoss Huperzia serrata. It is a potent acetylcholinesterase inhibitor, among other properties, and has demonstrated protection against induced seizures in a mouse model of Dravet's syndrome as well as nerve-agent induced seizures and is being explored as a novel anticonvulsant in a human clinical trial for focal impaired awareness seizures. It is also being explored as a treatment for Alzheimer's, via neuroprotective effects and an ability to ameliorate neuroinflammation. Here we present a case series of 6 dogs with idiopathic epilepsy treated with huperzine to investigate this potential novel anticonvulsant. Despite a 50% drop out rate over the course of the study due to various causes including unexplained death, humane euthanasia and systemic disease, huperzine was generally well tolerated and showed some positive effects on demeanor. This study highlights the need for more research to investigate its efficacy as a novel antiepileptic medication in dogs.

RevDate: 2025-03-28

Roy SM, Acquarone E, Argyrousi EK, et al (2025)

Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.

Alzheimer's & dementia (New York, N. Y.), 11(1):e70073.

INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.

RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and β-arrestin-1 recruitment.

DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.

HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.

RevDate: 2025-03-28

Hermans AMM, Bakker E, Starokozhko V, et al (2025)

Biomarkers for neurodegenerative diseases in regulatory decision-making by the European Medicines Agency.

Alzheimer's & dementia (New York, N. Y.), 11(1):e70072.

INTRODUCTION: Biomarkers (BMs) are valuable tools to facilitate early diagnosis of (subtypes of) diseases, improve patient selection and stratification, and detect therapeutic effects or safety concerns. This study explores the extent to which BMs are utilized in the development of treatments for neurodegenerative diseases (NDDs), as well as topics of discussion regarding BMs in regulatory advice- and decision-making processes and sharing of BM-related data.

METHODS: The European Medicines Agency's marketing authorization application (MAA), qualification (QA/QO), and scientific advice (SA) procedures regarding NDDs were screened, and those that mention BMs were analyzed. Data were extracted on the intended disease, BM type, and context of use proposed by applicants. BMs were categorized based on both nature and function.

RESULTS: In total, 105 procedures that discussed BMs were analyzed, 57 SAs (January 2020 to December 2022), 19 QAs/QOs (January 2008 to December 2023), and 29 MAAs (January 1995 to December 2023). The majority involved Alzheimer's disease (AD; n = 30), Parkinson's disease (PD; n = 9), and multiple sclerosis (MS; n = 33). Imaging BMs were the most common type of BMs discussed, and most BMs were used as pharmacodynamic/response measures. The acceptance and role of BMs differed between AD, PD, MS, and other NDDs. In regulatory procedures for AD, for example, diagnostic BMs guiding patient selection were commonly discussed, whereas in MAAs for MS, imaging BMs (particularly lesions) were generally accepted as supportive/secondary endpoints.

DISCUSSION: Despite the established role of certain BMs, mainly imaging BMs for MS, there remains a major need for more precise and reliable BMs to improve diagnostic accuracy and treatment monitoring for NDDs. To implement novel BMs and facilitate development of new treatments and to eventually improve clinical practice, robust evidence bases showcasing biological plausibility or clear clinical benefits are essential. Collaboration and data-sharing among stakeholders is vital in generating this evidence and enhancing the understanding and management of NDDs.

HIGHLIGHTS: The European Medicines Agency's marketing authorization applications and qualification and scientific advice procedures.One hundred five procedures were analyzed regarding neurodegenerative diseases that discuss biomarkers.We found that acceptance and role of biomarkers differ per disease.Biological plausibility/clinical benefits are essential for biomarker implementation.

RevDate: 2025-03-28

Nawaz A, Sadiq A, Bashir N, et al (2025)

Synthetic Derivates of Progesterone Ameliorate Scopolamine-Induced Cognitive Deficits in Animal Models: Antioxidant, Enzyme Inhibitory, Molecular Docking and Behavioral Correlates.

Current neuropharmacology pii:CN-EPUB-147413 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a neurological disorder characterized by cognitive decline and behavioral turbulence and is anticipated to badly affect the patient's quality of life. Previous studies revealed the neuroprotective effects of progesterone, so this study aimed to appraise the neuroprotective potentials of new derivatives of progesterone (AN-1 to AN-5).

METHODS: Subsequent to compound synthesis and structure elucidation, the in-vitro antioxidant (DPPH), acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory and molecular docking studies were performed following standard procedures. The most potent compound was subjected to more detailed behavioral studies, including Y-Maze, Elevated Plus Maze (EPM), and open field tests in scopolamine-induced amnesic animals.

RESULTS: In the DPPH assay, the AN-1 compound at 1000 μg/ml concentration exhibited 83.37 ± 2.03% inhibition of DPPH free radicals and an IC50 value of 24.81 μg/ml. Likewise, the compound AN-1 demonstrated 88.94 ± 1.20% inhibition against AChE and 86.78 ± 1.24% inhibition against BChE enzymes at 1000 μg/ml with IC50 values of 24.51 and 18.79 μg/ml, correspondingly. In behavioral studies, compound AN-1 demonstrated a significant decline in cognitive impairments and improved working memory as well as locomotor activities of the amnesic animals. Molecular docking studies also demonstrated that the compound AN-1 has promising inhibitory potentials against AChE and BChE enzymes by binding to their active sites. The binding energies of AN-1 with both enzymes were -7.6 Kcal/mol for AChE and -8.1 Kcal/mol for BChE.

CONCLUSION: Based on our findings, it is concluded that the derivatives of progesterone exhibit neuroprotective potential, and further research is needed to extend their neuroprotective role in the treatment of AD.

RevDate: 2025-03-28

Verwaerde P, O Defert (2025)

AZP2006 (Ezeprogind[®]): a Promising New Drug Candidate in the Battle Against Neurodegenerative Diseases.

ChemMedChem [Epub ahead of print].

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein accumulation. This perspective article explores AZP2006 (INN: Ezeprogind), a novel small molecule targeting the Progranulin (PGRN) and Prosaposin (PSAP) axis to enhance lysosomal health in PSP treatment. AZP2006 stabilizes the PGRN-PSAP complex, improving lysosomal function and reducing tau pathology. Preclinical studies in tauopathy models demonstrated AZP2006's ability to decrease tau hyperphosphorylation, enhance neuronal survival, mitigate neuroinflammation and promote synaptogenesis. Clinical trials have shown AZP2006 to be well-tolerated in healthy volunteers and PSP patients. A Phase 2a study met its primary endpoints, as it provided valuable safety data and even encouraged further investigation of its efficacy in a larger clinical study. An upcoming Phase 2b/3 trial aims to assess long-term safety and efficacy in a larger PSP cohort. AZP2006's mechanism of action strongly suggests potential applications in other tauopathies, including Alzheimer's and Parkinson's diseases. By addressing lysosomal dysfunction and tau pathology, AZP2006 represents a promising disease-modifying approach for PSP and other neurodegenerative disorders.

RevDate: 2025-03-28

Muksimova S, Umirzakova S, Baltayev J, et al (2025)

Multi-Modal Fusion and Longitudinal Analysis for Alzheimer's Disease Classification Using Deep Learning.

Diagnostics (Basel, Switzerland), 15(6): pii:diagnostics15060717.

Background: Addressing the complex diagnostic challenges of Alzheimer's disease (AD), this study introduces FusionNet, a groundbreaking framework designed to enhance AD classification through the integration of multi-modal and longitudinal imaging data. Methods: FusionNet synthesizes inputs from Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), and Computed Tomography (CT) scans, harnessing advanced machine learning strategies such as generative adversarial networks (GANs) for robust data augmentation, lightweight neural architectures for efficient computation, and deep metric learning for precise feature extraction. The model uniquely combines cross-sectional and temporal data, significantly enhancing diagnostic accuracy and enabling the early detection and ongoing monitoring of AD. The FusionNet architecture incorporates specialized feature extraction pathways for each imaging modality, a fusion layer to integrate diverse data sources effectively, and attention mechanisms to focus on salient diagnostic features. Results: Demonstrating superior performance, FusionNet achieves an accuracy of 94%, with precision and recall rates of 92% and 93%, respectively. Conclusions: These results underscore its potential as a highly reliable diagnostic tool for AD, facilitating early intervention and tailored treatment strategies. FusionNet's innovative approach not only improves diagnostic precision but also offers new insights into the progression of Alzheimer's disease, supporting personalized patient care and advancing our understanding of this debilitating condition.

RevDate: 2025-03-28

Chen Y, Xiao D, X Li (2025)

Lactylation and Central Nervous System Diseases.

Brain sciences, 15(3): pii:brainsci15030294.

As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer's disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.

RevDate: 2025-03-28

Singh AA, Katiyar S, M Song (2025)

Phytochemicals Targeting BDNF Signaling for Treating Neurological Disorders.

Brain sciences, 15(3): pii:brainsci15030252.

Neurological disorders are defined by a deterioration or disruption of the nervous system's structure and function. These diseases, which include multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and schizophrenia, are caused by intricate pathological processes that include excitotoxicity, neuroinflammation, oxidative stress, genetic mutations, and compromised neurotrophic signaling. Although current pharmaceutical treatments relieve symptoms, their long-term efficacy is limited due to adverse side effects and weak neuroprotective properties. However, when combined with other neuroprotective drugs or adjunct therapy, they may offer additional benefits and improve treatment outcomes. Phytochemicals have emerged as attractive therapeutic agents due to their ability to regulate essential neurotrophic pathways, especially the brain-derived neurotrophic factor (BDNF) signaling cascade. BDNF is an important target for neurodegenerative disease (ND) treatment since it regulates neuronal survival, synaptic plasticity, neurogenesis, and neuroprotection. This review emphasizes the molecular pathways through which various phytochemicals-such as flavonoids, terpenoids, alkaloids, and phenolic compounds-stimulate BDNF expression and modulate its downstream signaling pathways, including GSK-3β, MAPK/ERK, PI3K/Akt/mTOR, CREB, and Wnt/β-catenin. This paper also highlights how phytochemical combinations may interact to enhance BDNF activity, offering new therapeutic options for ND treatment. Despite their potential for neuroprotection, phytochemicals face challenges related to pharmacokinetics, blood-brain barrier (BBB) permeability, and absorption, highlighting the need for further research into combination therapies and improved formulations. Clinical assessment and mechanistic understanding of BDNF-targeted phytotherapy should be the main goals of future studies. The therapeutic efficacy of natural compounds in regulating neurotrophic signaling is highlighted in this review, providing a viable approach to the prevention and treatment of NDs.

RevDate: 2025-03-28

Ortiz GG, González-Usigli H, Nava-Escobar ER, et al (2025)

Primary Progressive Aphasias: Diagnosis and Treatment.

Brain sciences, 15(3): pii:brainsci15030245.

Background and Objective: Primary Progressive Aphasias (PPAs) are rare neurodegenerative disorders classified within frontotemporal lobar degeneration (FTLD) and typically manifest between 45 and 70 years of age. In Mexico-and many other countries-reliable epidemiological data are lacking; however, estimates suggest that PPA accounts for 0.5-2.5% of neurodegenerative disease cases in Memory Clinics, with an incidence of approximately 1 per 100,000 and an average survival of 8 years. This review aims to provide clinicians with an overview of PPA's epidemiology, clinical features, and classification, thereby enhancing understanding of its subtypes and distinguishing characteristics from other aphasic conditions, such as vascular aphasia. Methods: This narrative review was conducted through a literature search using databases such as PubMed and Scopus. Relevant studies addressing the epidemiology, clinical presentation, and classification of PPA were identified, selected, and synthesized to offer a broad, clinically oriented overview of the condition. This approach was chosen to inform clinical practice and highlight the need for further targeted investigations, such as future systematic reviews focusing on specific aspects like therapeutic strategies. Key Contents and Findings: (a) Epidemiology: PPA is estimated to affect 0.5-2.5% of patients with neurodegenerative diseases in Memory Clinics, with an incidence of roughly 1 per 100,000. Average survival time is around 8 years (ranging from 3 to 17 years), with a generally balanced gender ratio, though some studies indicate a predominance of men. A positive family history is observed in 20-40% of cases, with about 10% following an autosomal dominant inheritance pattern. (b) Clinical Characteristics and Classification: PPA is marked by a gradual decline in language abilities, differentiating it from vascular aphasias. Subtypes include non-fluent forms (non-fluent progressive aphasia [nfPPA] and logopenic progressive aphasia [lPPA]), fluent forms (progressive fluent aphasia [PFA] and semantic dementia [SD]), and mixed forms (progressive mixed aphasia [PMA]). The neurodegenerative process in PPA extends beyond vascular boundaries, often resulting in presentations that deviate from classical Broca's and Wernicke's aphasias. Common symptoms include difficulties in word finding and naming, sometimes mistaken for memory loss, and, in the case of semantic dementia, personality changes that may go unnoticed by the patient. Conclusions: PPA is a heterogeneous and complex group of neurodegenerative disorders with significant clinical variability and a profound impact on patients and their families. While current epidemiological data are limited, this review emphasizes the need for further research to better delineate disease progression and refine diagnostic and therapeutic approaches. Future systematic reviews will be essential to address specific aspects of PPA, such as treatment strategies, to further improve patient care.

RevDate: 2025-03-28

Weidauer S, E Hattingen (2025)

Cerebral Amyloid Angiopathy: Clinical Presentation, Sequelae and Neuroimaging Features-An Update.

Biomedicines, 13(3): pii:biomedicines13030603.

The prevalence of cerebral amyloid angiopathy (CAA) has been shown to increase with age, with rates reported to be around 50-60% in individuals over 80 years old who have cognitive impairment. The disease often presents as spontaneous lobar intracerebral hemorrhage (ICH), which carries a high risk of recurrence, along with transient focal neurologic episodes (TFNE) and progressive cognitive decline, potentially leading to Alzheimer's disease (AD). In addition to ICH, neuroradiologic findings of CAA include cortical and subcortical microbleeds (MB), cortical subarachnoid hemorrhage (cSAH) and cortical superficial siderosis (cSS). Non-hemorrhagic pathologies include dilated perivascular spaces in the centrum semiovale and multiple hyperintense lesions on T2-weighted magnetic resonance imaging (MRI). A definitive diagnosis of CAA still requires histological confirmation. The Boston criteria allow for the diagnosis of a probable or possible CAA by considering specific neurological and MRI findings. The recent version, 2.0, which includes additional non-hemorrhagic MRI findings, increases sensitivity while maintaining the same specificity. The characteristic MRI findings of autoantibody-related CAA-related inflammation (CAA-ri) are similar to the so-called "amyloid related imaging abnormalities" (ARIA) observed with amyloid antibody therapies, presenting in two variants: (a) vasogenic edema and leptomeningeal effusions (ARIA-E) and (b) hemorrhagic lesions (ARIA-H). Clinical and MRI findings enable the diagnosis of a probable or possible CAA-ri, with biopsy remaining the gold standard for confirmation. In contrast to spontaneous CAA-ri, only about 20% of patients treated with monoclonal antibodies who show proven ARIA on MRI also experience clinical symptoms, including headache, confusion, other psychopathological abnormalities, visual disturbances, nausea and vomiting. Recent findings indicate that treatment should be continued in cases of mild ARIA, with ongoing MRI and clinical monitoring. This review offers a concise update on CAA and its associated consequences.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Poniah P, Abdul Rashed A, Abdul Jalil J, et al (2025)

Clinical Significance of Early-Onset Alzheimer's Mutations in Asian and Western Populations: A Scoping Review.

Genes, 16(3): pii:genes16030345.

BACKGROUND/OBJECTIVES: Background: Early-onset Alzheimer's disease (EOAD) is primarily inherited in an autosomal dominant pattern, with mutations in the APP, PSEN1, and PSEN2 genes being central contributors. Diagnosing Alzheimer's poses challenges due to the coexistence of various co-pathologies, and treatment options remain limited for most patients, apart from familial cases linked to specific genetic mutations. While significant research on Alzheimer's genetics has been conducted in both Asian and Caucasian populations, the specific mutations and their clinical impacts in EOAD are still inadequately explored. This review aims to provide a detailed analysis of commonly reported genetic mutations and associated clinical features in EOAD patients from Asian and Western populations.

METHODS: Following the PRISMA-ScR guidelines, a systematic database search was conducted for studies published between 2016 and 2023. After screening 491 records, 36 studies from Asian cohorts and 40 from Western cohorts met the inclusion criteria.

RESULTS: The analysis revealed 127 unique mutations in the Asian population and 190 in the Western population. About 16.7% of Asian and 21.9% of Western studies covered both familial and sporadic AD, with consistent patterns across groups. Some mutations were shared between the populations and displayed similar clinical features, while others were population-specific.

CONCLUSIONS: These findings underscore the considerable variability in EOAD mutations and phenotypes, emphasizing the importance of genetic testing in younger patients to enhance diagnostic accuracy and guide treatment strategies effectively.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Simonyan K, Darbinyan L, Hambardzumyan L, et al (2025)

Teucrium Polium ameliorates amyloid β-induced brain network disorders in rats: electrophysiological and behavioral studies.

BMC complementary medicine and therapies, 25(1):116.

Synaptic failure in specific cholinergic networks in rat brains has been implicated in amyloid β-induced neurodegeneration. Teucrium polium is a promising candidate for drug development against Alzheimer's disease (AD) and similar disorders. However, the protective effect of Teucrium polium against amyloid β-induced impairment of short-term synaptic plasticity is still poorly understood. In this study, we used in vivo extracellular single-unit recordings to investigate the preventive efficacy of Teucrium polium on Aβ(25-35)-induced aberrant neuronal activity in the hippocampus and basolateral amygdala of rats, in response to high-frequency stimulation of the cholinergic nucleus basalis magnocellularis (NBM). After 12 weeks of intracerebroventricular administration of Aβ(25-35), alterations such as decreased excitatory responses and increased inhibitory synaptic activity were observed in the NBM-hippocampus and NBM-basolateral amygdala cholinergic circuits. Treatment with Teucrium polium improved the balance of excitatory and inhibitory responses by modulating synaptic transmission strength and restoring short-term plasticity. Acute injection of a therapeutic dose of Teucrium temporarily inhibited spiking activity in single NBM neurons. Open field tests revealed that amyloid-injected rats displayed anxiety and reduced exploratory drive. Treatment with Teucrium polium improved these behaviors, reducing anxiety and increasing exploration. Teucrium polium mitigated amyloid β-induced alterations in cholinergic circuits by enhancing the adaptive capacity of short-term synaptic plasticity. These findings suggest that Teucrium polium could serve as a preventive strategy to delay the progression of cholinergic neurodegeneration.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Liu J, Yan M, Chen L, et al (2025)

Construction and evaluation of a diagnostic model for Alzheimer's disease based on mitophagy-related genes.

Scientific reports, 15(1):10632.

Alzheimer's disease (AD) is the most common cause of dementia. Mitophagy fulfills crucial functions in neurodegenerative disorders and neuronal survival but the relationship between mitophagy and AD is unclear. Mitophagy correlation scores between AD samples and control samples were calculated using single-sample GSEA (ssGSEA) based on two datasets from gene expression omnibus (GEO) database. Mitophagy-related genes (MRGs) and differentially expressed genes (DEGs) in AD screened by WGCNA and "limma" package were intersected to take common genes. These overlapping genes were further compressed and used for diagnostic modeling by adopting the recursive feature elimination (RFE) and LASSO analysis. The reliability of the diagnostic model was verified based on the receiver operating characteristic (ROC) curve. Then, a transcription factor (TF)-mRNA regulatory network of these key genes was established. Lastly, ssGSEA was employed to examine the relationship between the identified genes and cellular pathways and immune cell infiltration. AD samples had notably lower mitophagy correlation scores than control samples. A total of 12 MRGs in the module with the greatest mitophagy connection with AD patients were identified. Functional enrichment analysis revealed that the DEGs were significantly enriched in synaptic function-related pathways. Based on GSE122063, a diagnostic prediction model was created and validated using two mitophagy-related genes (YWHAZ and NDE1), showing an area under ROC curve (AUC) greater than 0.7. This confirmed that the diagnostic model had a high predictive value. The TF-mRNA network showed that four TFs, namely, FOXC1, FOXL1, HOXA5 and GATA2, were regulated by both YWHAZ and NDE1 genes. Immune infiltration analysis revealed that NDE1 promoted the infiltration of most immune cells, while YWHAZ mainly inhibited the infiltration of most immune cells. The current findings improved our understanding of mitophagy in AD, contributing to future research and treatment development in AD.

RevDate: 2025-03-27

Lee SK, Han M, Park S, et al (2025)

Association of Physical Activity with Dementia Risk in Cancer Survivors: A Korean Nationwide Cohort Study.

Cancer research and treatment pii:crt.2024.901 [Epub ahead of print].

PURPOSE: This study aimed to investigate the impact of physical activity on dementia risk among cancer survivors in South Korea.

MATERIALS AND METHODS: This retrospective, population-based cohort study included 344,152 cancer survivors identified from the National Health Insurance Service database in South Korea. The mean follow-up time was 5.81 years. Different levels of physical activity post-cancer diagnosis, ranging from inactive to highly active, were assessed. The primary outcome was the incidence of overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Secondary outcomes included dementia risk stratified by cancer type and treatment (chemotherapy and radiation).

RESULTS: Of the total participants, 24,363 (7.08%) developed dementia. The risk of overall dementia decreased sequentially across the exercise groups compared to the inactive group: insufficiently active (adjusted HR, 0.89; 95% CI, 0.86-0.92), active (adjusted HR, 0.85; 95% CI, 0.83-0.88), and highly active (adjusted HR, 0.79; 95% CI, 0.76-0.82). This inverse relationship between exercise and dementia risk was statistically significant across various cancer types and was consistent regardless of age, comorbidities, and whether or not excluding the first 1, 2 years.

CONCLUSION: Among cancer survivors in South Korea, increased physical activity post-diagnosis was associated with a significantly lower risk of dementia. These findings underscore the importance of promoting physical activity in cancer survivors for cognitive health.

RevDate: 2025-03-27

Li C, Gao Z, Chen X, et al (2025)

Ensemble network using oblique coronal MRI for Alzheimer's disease diagnosis.

NeuroImage pii:S1053-8119(25)00153-3 [Epub ahead of print].

Alzheimer's disease (AD) is a primary degenerative brain disorder commonly found in the elderly, Mild cognitive impairment (MCI) can be considered a transitional stage from normal aging to Alzheimer's disease. Therefore, distinguishing between normal aging and disease-induced neurofunctional impairments is crucial in clinical treatment. Although deep learning methods have been widely applied in Alzheimer's diagnosis, the varying data formats used by different methods limited their clinical applicability. In this study, based on the ADNI dataset and previous clinical diagnostic experience, we propose a method using oblique coronal MRI to assist in diagnosis. We developed an algorithm to extract oblique coronal slices from 3D MRI data and used these slices to train classification networks. To achieve subject-wise classification based on 2D slices, rather than image-wise classification, we employed ensemble learning methods. This approach fused classification results from different modality images or different positions of the same modality images, constructing a more reliable ensemble classification model. The experiments introduced various decision fusion and feature fusion schemes, demonstrating the potential of oblique coronal MRI slices in assisting diagnosis. Notably, the weighted voting from decision fusion strategy trained on oblique coronal slices achieved accuracy rates of 97.5% for CN vs. AD, 100% for CN vs. MCI, and 94.83% for MCI vs. AD across the three classification tasks.

RevDate: 2025-03-27

Sharma V, Reang J, Yadav V, et al (2025)

Discovery of 6-amino pyridine clubbed heterocycles as potent dual GSK-3β/CK-1δ inhibitors for the treatment of Alzheimer's disease.

Bioorganic chemistry, 159:108409 pii:S0045-2068(25)00289-5 [Epub ahead of print].

Alzheimer's disease (AD) is a progressive and chronic neurodegenerative disorder progression through various kinases. Glycogen synthase kinase 3β (GSK-3β) and Casein Kinase-1δ (CK-1δ) have gained a lot of attention for its role in tau pathology. Utilizing a multitarget strategy, a series of 6-amino pyridine derivatives were developed as promising dual GSK-3β/CK-1δ inhibitors for the treatment of AD. This study involved the design, synthesis, and evaluation of novel 6-amino pyridine derivatives as dual GSK-3β/CK-1δ inhibitors exhibiting excellent biological activities. The in-vitro results indicated that most of compounds displayed promising activity against GSK-3β/CK-1δ. Among the tested compounds, 8d exhibited strong inhibitory activity against GSK-3β and CK-1δ, with IC50 values of 0.77 ± 0.01 μM and 0.57 ± 0.12 μM, respectively. Notably, compound 8d significantly reduced tau hyperphosphorylated aggregates while demonstrating safety in SH-SY5Y neuroblastoma cell lines. ADME prediction results indicated that compound 8d adhered to Lipinski's rule of five and exhibited potential to permeate the blood-brain barrier (BBB). Molecular docking analysis revealed that this compound fits well within the ATP binding site, forming hydrogen bonds between its 6-amino pyridine ring with key amino acids, including Asp133 and Val135 in the hinge region of GSK-3β, as well as Leu85 of CK-1δ. These findings indicate that 6-amino pyridine derivatives have the potential to be effective dual-target candidates for AD.

RevDate: 2025-03-27

Zhao W, Liu Z, Wu J, et al (2025)

Potential targets of microglia in the treatment of neurodegenerative diseases: mechanism and therapeutic implications.

Neural regeneration research pii:01300535-990000000-00748 [Epub ahead of print].

For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial overactivation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Ruthirakuhan M, Guan DX, Mortby M, et al (2025)

Updates and future perspectives on neuropsychiatric symptoms in Alzheimer's disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(3):e70079.

Neuropsychiatric symptoms (NPS) are common throughout the Alzheimer's disease (AD) continuum and profoundly affect patients, caregivers, and health-care systems. This review synthesizes key research presented in the 2022 and 2023 Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Neuropsychiatric Syndromes-Professional Interest Area (NPS-PIA) Year-In-Reviews, emphasizing six critical areas: (1) diversity and disparities, (2) diagnostic frameworks, (3) neurobiology of NPS, (4) NPS as a disease marker, (5) the impact of COVID-19, and (6) interventions. NPS accelerates AD progression, increases functional decline, diminishes quality of life, and heightens caregiver burden and institutionalization rates. Current treatments primarily rely on psychotropics, which offer limited efficacy and raise safety concerns. This review aims to inform clinicians and researchers about recent NPS advancements while identifying gaps for future studies to improve outcomes for individuals with AD. HIGHLIGHTS: Research in Alzheimer's disease-related neuropsychiatric symptoms has rapidly increased, indicating heightened interest. Key areas include: diversity, diagnostics, markers, COVID-19 impact, and treatments. A road map for future studies, based on the key areas of research, is provided. This road map includes considerations to improve study applicability and validity.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Hazan J, Liu KY, Isaacs JD, et al (2025)

Cut-points and gray zones: The challenges of integrating Alzheimer's disease plasma biomarkers into clinical practice.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(3):e70113.

Plasma biomarkers for Alzheimer's disease (AD), such as plasma phosphorylated (p)-tau217, offer a more accessible means of testing for the presence of AD pathology compared to cerebrospinal fluid (CSF) or positron emission tomography (PET) methods. They can support diagnostic assessment and determine patient eligibility for treatment with amyloid beta-lowering drugs in community settings where access to CSF examination and amyloid-PET are limited. However, there are important challenges associated with interpreting and integrating plasma biomarker results in clinical practice. This article explores different approaches to interpreting plasma biomarker results in secondary care, important potential sources of uncertainty, and considerations for their clinical application. HIGHLIGHTS: Plasma biomarkers such as phosphorylated tau-217 (p-tau217) offer a promising, accessible alternative to cerebrospinal fluid (CSF) and positron emission tomography (PET) for detecting Alzheimer's disease pathology, especially in settings with limited diagnostic resources. Clinical integration of plasma biomarker testing presents challenges, particularly in interpreting results. This includes uncertainties around intermediate results and their role in patient management. Clear frameworks and guidelines are essential to optimize the use of plasma biomarkers, supported by further research and education to ensure effective application in clinical practice.

RevDate: 2025-03-28

Han L (2025)

AD-Diff: enhancing Alzheimer's disease prediction accuracy through multimodal fusion.

Frontiers in computational neuroscience, 19:1484540.

Early prediction of Alzheimer's disease (AD) is crucial to improving patient quality of life and treatment outcomes. However, current predictive methods face challenges such as insufficient multimodal information integration and the high cost of PET image acquisition, which limit their effectiveness in practical applications. To address these issues, this paper proposes an innovative model, AD-Diff. This model significantly improves AD prediction accuracy by integrating PET images generated through a diffusion process with cognitive scale data and other modalities. Specifically, the AD-Diff model consists of two core components: the ADdiffusion module and the multimodal Mamba Classifier. The ADdiffusion module uses a 3D diffusion process to generate high-quality PET images, which are then fused with MRI images and tabular data to provide input for the Multimodal Mamba Classifier. Experimental results on the OASIS and ADNI datasets demonstrate that the AD-Diff model performs exceptionally well in both long-term and short-term AD prediction tasks, significantly improving prediction accuracy and reliability. These results highlight the significant advantages of the AD-Diff model in handling complex medical image data and multimodal information, providing an effective tool for the early diagnosis and personalized treatment of Alzheimer's disease.

RevDate: 2025-03-28

Wang W, Ye J, Wei Y, et al (2025)

Clinical characteristics of schizophrenia, depression, and Alzheimer's diseases among older adults: a retrospective study of 271 consecutive admissions.

Frontiers in psychiatry, 16:1486626.

OBJECTIVE: This study aims to identify the clinical characteristics of schizophrenia, depression, and AD among older adults.

METHODS: General information of patients was collected, including diagnosis, age, gender, level of education, marital status, drinking behavior, smoking behavior, course of mental disorder, type of admission, history of modified electroconvulsive therapy (MECT) and hospitalization period. The Brief Psychiatric Rating Scale (BPRS), Geriatric Depression Scale (GDS), Generalized Anxiety Disorder 7-Item Scale (GAD-7), Insight and Treatment Attitudes Questionnaire (ITAQ), and Mini-Mental State Examination (MMSE) were employed to evaluate the participants' mental status. The Functional Activities Questionnaire (FAQ), Social Support Rating Scale (SSRS), Barthel ADL Index, Standardized Swallowing Assessment (SSA), and Mini-Nutritional Assessment (MNA) were applied to measure social and daily living function. The Nurses' Global Assessment of Suicide Risk (NGASR) and The Brøset Violence Checklist (BVC) were used to assess the patients' risk of suicide.

RESULTS: Totally 271 participants were recruited, the numbers of participants with schizophrenia, depression, and Alzheimer's diseases (AD), were 81 (29.9%), 85 (31.4%), and 105 (38.7%), respectively. One-way ANOVA was used to compare the variance of the crude score results among three groups of subjects. The results showed that patients with depression had the highest GDS total score, followed by patients with AD, and patients with schizophrenia had the lowest score (P < 0.001). The total scores of GAD-7 and ITAQ in patients with depression were higher than those in patients with AD and schizophrenia (P < 0.001). The total score of MMSE in patients with schizophrenia and depression was higher than that in patients with AD (P < 0.001). The incidence of circulatory system diseases in patients with depression and AD was higher than that in patients with schizophrenia (P < 0.05). The incidence of respiratory system diseases in patients with AD was highest, followed by patients with schizophrenia, and patients with depression had the lowest incidence (P < 0.05). The incidence of nervous system diseases in patients with AD was highest, followed by patients with depression, and patients with schizophrenia had the lowest incidence (P < 0.05). The total scores of FAQ and SSA in patients with AD were higher than those in patients with schizophrenia and depression (P < 0.001), while patients with depression had statistically lower SSRS scores than patients with schizophrenia and patients with AD (P < 0.05). Furthermore, patients with AD had lower Barthel ADL Index scores and water-swallowing test (P < 0.001). MNA scores of patients with schizophrenia were higher than those of patients with depression and AD, with statistical significance (P < 0.05). The NGASR scores of patients with depression were higher than those of patients with schizophrenia and AD, which was statistically significant (P < 0.001). Patients with AD had the highest BVC total score, followed by that of patients with schizophrenia and patients with depression had lowest score, and the difference was statistically significant (P < 0.05).

CONCLUSIONS: Patients with geriatric psychosis may experience abnormalities in various aspects that influenced daily living, including disorders of thinking, cognition, emotion, and behavior. Patients with schizophrenia have cognitive impairment. Cognitive training and medication are important. Patients with depression were considered to be at a greater risk for suicide compared to those with schizophrenia and AD. Active clinical measures must be adopted to improve patients' depressive symptoms, change their suicidal attitudes, and enhance their self-confidence. Patients with AD were prone to respiratory and neurological diseases. Treatment of respiratory infections and hypoxia and other respiratory diseases would be necessary, and cognitive function training should be conducted. In addition, regarding to high risk of swallowing disorders and malnutrition, swallowing function training should be carried out to ensure food intake and prevent malnutrition. Driven by psychiatric symptoms, violent behavior was prevalent, thus effective communication and de-escalation techniques are needed. Although the symptoms of these three diseases are different, timely professional intervention and support from family members are urgently needed.

RevDate: 2025-03-27

Évora A, Garcia G, Rubi A, et al (2025)

Exosomes enriched with miR-124-3p show therapeutic potential in a new microfluidic triculture model that recapitulates neuron-glia crosstalk in Alzheimer's disease.

Frontiers in pharmacology, 16:1474012.

BACKGROUND: Alzheimer's disease (AD), a complex neurodegenerative disease associated with ageing, is the leading cause of dementia. Few people with early AD are eligible for the novel Food and Drug Administration (FDA)-approved drug treatments. Accordingly, new tools and early diagnosis markers are required to predict subtypes, individual stages, and the most suitable personalized treatment. We previously demonstrated that the regulation of microRNA (miR)-124 is crucial for proper neuronal function and microglia reshaping in human AD cell models.

OBJECTIVE: The aim of this study was to develop an efficient miR-124-3p-loaded exosome strategy and validate its therapeutic potential in using a multi-compartment microfluidic device of neuron-glia that recapitulates age-AD pathological features.

METHODS AND RESULTS: Using cortical microglia from mouse pups, separated from glial mixed cultures and maintained for 2 days in vitro (stressed microglia), we tested the effects of SH-SY5Y-derived exosomes loaded with miR-124-3p mimic either by their direct transfection with Exo-Fect™ (ET124) or by their isolation from the secretome of miR-124 transfected cells (CT124). ET124 revealed better delivery effciency and higher potent effects in improving the stressed microglia status than CT124. Tricultures of human SH-SY5Y neuroblastoma cells (SH-WT) were established in the presence of the human microglia cell line (HMC3) and immortalized human astrocytes (IM-HA) in tricompartmentalized microfluidic devices. Replacement of SH-WT cells with those transfected with APP695 (SH-SWE) in the tricultures and addition of low doses of hydrogen peroxide were used to simulate late-onset AD. The system mimicked AD-associated neurodegeneration and neuroinflammation processes. Notably, ET124 exhibited neuroprotective properties across the three cell types in the AD model by preventing neuronal apoptosis and neurite deficits, redirecting microglial profiles towards a steady state, and attenuating the inflammatory and miRNA fingerprints associated with astrocyte reactivity.

CONCLUSION: To the best of our knowledge, this is the first study supporting the neuro- and immunoprotective properties of miR-124-engineered exosomes in a microfluidic triculture platform, recapitulating age-related susceptibility to AD. Our system offers potential to develop personalized medicines in AD patient subtypes.

RevDate: 2025-03-27

Zeng R, Yang B, Wu F, et al (2025)

Early prediction of Alzheimer's disease using artificial intelligence and cortical features on T1WI sequences.

Frontiers in neurology, 16:1552940.

BACKGROUND: Accurately predicting the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) is a challenging task, which is crucial for helping develop personalized treatment plans to improve prognosis.

PURPOSE: To develop new technology for the early prediction of AD using artificial intelligence and cortical features on MRI.

METHODS: A total of 162 MCI patients were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. By using a 3D-MPRAGE sequence, T1W images for each patient were acquired. All patients were randomly divided into a training set (n = 112) and a validation set (n = 50) at a ratio of 7:3. Morphological features of the cerebral cortex were extracted with FreeSurfer software. Network features were extracted from gray matter with the GRETNA toolbox. The network, morphology, network-clinical, morphology-clinical, morphology-network and morphology-network-clinical models were developed by multivariate Cox proportional hazard model. The performance of each model was assessed by the concordance index (C-index).

RESULTS: In the training group, the C-indexes of the network, morphology, network-clinical, morphology-clinical, morphology-network and morphology-network-clinical models were 0.834, 0.926, 0.915, 0.949, 0.928, and 0.951, respectively. The C-indexes of those models in the validation group were 0.765, 0.784, 0.849, 0.877, 0.884, and 0.880, respectively. The morphology-network-clinical model performed the best. A multi-predictor nomogram with high accuracy for individual AD prediction (C-index = 0.951) was established.

CONCLUSION: The early occurrence of AD could be accurately predicted using our morphology-network-clinical model and the multi-predictor nomogram. This could help doctors make early and personalized treatment decisions in clinical practice, which showed important clinical significance.

RevDate: 2025-03-27

Zhang H, Ya J, Sun M, et al (2025)

Inhibition of the cGAS-STING pathway via an endogenous copper ion-responsive covalent organic framework nanozyme for Alzheimer's disease treatment.

Chemical science [Epub ahead of print].

Inhibition of cGAS-STING overactivation has recently emerged as a promising strategy to counteract Alzheimer's disease (AD). However, current cGAS-STING inhibitors as immunosuppressants suffer from instability, non-specific targeting, and innate immune disruption. Here, an endogenous AD brain copper ion-responsive covalent organic framework (COF)-based nanozyme (denoted as TP@PB-COF@NADH) has been designed for targeted inhibition of the cGAS-STING pathway for AD treatment. The effective trapping of excess brain endogenous copper ions by TP@PB-COF@NADH not only inhibits the Cu[2+]-induced harmful reactive oxygen species (ROS) production which is one of the mediators of cGAS-STING activation, but also activates the nanozyme activity of TP@PB-COF@NADH. Furthermore, the well-prepared nanozyme catalytically generates NAD[+] and consumes hydrogen peroxide (H2O2) through second near-infrared (NIR-II) enhanced nicotinamide adenine dinucleotide (NADH) peroxidase (NPX)-like activity, realizing the efficient inhibition of the cGAS-STING pathway and associated neuroinflammation. Moreover, replenishing NAD[+] levels efficiently restores mitochondrial function and ATP supply. In vivo studies demonstrate that TP@PB-COF@NADH with NIR-II irradiation significantly improves cognitive function in 3× Tg-AD mice, with a reduction in amyloid-β (Aβ) plaque, neuroinflammation and neuronal damage. Collectively, this work presents a promising approach for AD treatment by using an AD brain harmful excess endogenous copper ion-responsive and efficient nanozyme.

RevDate: 2025-03-27

Pradeep S, Sai Chakith MR, Sindhushree SR, et al (2025)

Exploring shared therapeutic targets for Alzheimer's disease and glioblastoma using network pharmacology and protein-protein interaction approach.

Frontiers in chemistry, 13:1549186.

BACKGROUND: Alzheimer's disease (AD) and glioblastoma (GBM) are complex neurological disorders with distinct pathologies but overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and dysregulated signaling pathways. Despite significant advancements in research, effective therapies targeting both conditions remain elusive. Identifying shared molecular targets and potential therapeutic agents could offer novel treatment strategies for these disorders.

METHODOLOGY: The study employs an integrative network pharmacology approach to explore the therapeutic potential of bioactive compounds from Eclipta alba, a medicinal herb known for its neuroprotective and anti-inflammatory properties. A systematic methodology was adopted, starting with network pharmacology analysis using STRING and DisGeNET databases, which identified 617 common genes associated with AD and GBM. Among these, key hub genes-TP53, STAT3, AKT1, and IL6-were prioritized using Cytoscape for network visualization and analysis.

RESULTS: Molecular docking studies were conducted using PyRx software to assess the binding interactions of 26 phytochemicals from Eclipta alba against the identified target genes. Luteolin exhibited the highest binding affinity to IL6 (-7.8 kcal/mol), forming stable hydrogen bonds and hydrophobic interactions. To further validate this interaction, molecular dynamics simulations (MDS) were performed using GROMACS, confirming the stability of the Luteolin-IL6 complex. Additionally, MM-PBSA binding energy calculations using AmberTools (-145.44 kJ/mol) provided further evidence of a strong and stable interaction. Pharmacokinetic and toxicity evaluations, conducted using SwissADME and pkCSM, highlighted luteolin's favorable drug-like properties, including good bioavailability and low toxicity. These findings suggest that luteolin may serve as a promising multi-target therapeutic agent for AD and GBM by modulating key pathological pathways.

CONCLUSION: The present study provides a strong computational foundation for further in vitro and in vivo validation. The results highlight the potential of luteolin in developing dual-target treatment strategies for neurodegenerative and oncological disorders, offering new avenues for therapeutic advancements.

RevDate: 2025-03-27

Lithgow BJ, Saha C, Dastgheib Z, et al (2025)

Surface Versus Penetrative rTMS Stimulation May Be More Effective for AD Patients with Cerebrovascular Disease.

Neuroscience insights, 20:26331055251328355.

Repetitive Transcranial Magnetic Stimulation (rTMS) has been applied as an investigational therapy for Alzheimer's Disease (AD). The recent largest (N = 135) double-blind study with 6 months post-treatment follow-up investigating rTMS efficacy as a treatment for AD found about 72% of participants in each group of active and sham were positively responsive to rTMS (using Magstim AirFilm active and sham coils). Since the used sham coil produced about 25.3% of the peak active stimulus, it was hypothesized it could evoke a measurable response in AD patients. This study looks at the details of the above study's sham responses to determine why and how such a response might occur and how cerebrovascular symptomatology may have impacted that response. In the above-mentioned study, 90 and 45 patients were randomly assigned to active and sham groups, respectively. Those with modified Hachinski Ischemic Scores (HIS) below and above 2 were labeled AD2 and ADcvd2, respectively. Analysis of the primary outcome measure ADAS-Cog score change from baseline to post-treatment and follow-ups showed the ADcvd2 in the sham group had a significantly (p = .034) greater improvement or less decline at post-treatment and follow-up sessions compared to the ADcvd2 in the active group. Additionally, the improvement of the ADcvd2 sham compared to those in the active group persisted longer. Also, there was a significant (p = .036) improvement for AD2 individuals in the active compared to AD2 sham stimulation group at 2-months post-treatment. Overall, the sham rTMS stimulus did evoke a measurable response which was more effective for ADcvd2 in sham than ADcvd2 in active support of a vascular mechanism likely linked to the shallower sham stimulus penetration.

RevDate: 2025-03-27

Alanazi MM, Albaker AB, Alzaagi LA, et al (2025)

Oxytocin Protects PC12 Cells Against β-Amyloid-Induced Cell Injury.

Pharmaceuticals (Basel, Switzerland), 18(3): pii:ph18030390.

Background/Objectives: Neurodegenerative diseases, particularly Alzheimer's disease (AD), are characterized by progressive cognitive decline and non-cognitive symptoms that significantly affect health and quality of life. Beta-amyloid (Aβ) protein accumulation is a key factor in AD pathology, leading to neuronal damage. Oxytocin (OXT), a neuropeptide with neuroprotective potential, has garnered interest owing to its ability to mitigate neurotoxicity. We hypothesized that oxytocin could protect PC12 cells from Aβ-induced cytotoxicity through antioxidant effects and modulation of apoptotic pathways (i.e., mitochondrial and MAPK pathways). In this study, we aim to assess oxytocin's protective effects on cell viability, oxidative stress, mitochondrial function, and apoptotic signaling. Methods: PC12 cells were treated with Aβ25-35 and pre-treated with varying oxytocin concentrations to assess cell viability, reactive oxygen species (ROS) generation, and mitochondrial membrane potential. Western blotting was performed to analyze the effects on mitochondrial apoptosis and MAPK pathways. Results: Oxytocin treatment significantly improved cell viability in a dose-dependent manner and reduced Aβ-induced oxidative stress and mitochondrial dysfunction. Oxytocin-treated groups exhibited decreased ROS levels, increased mitochondrial membrane potential, and modulation of apoptosis-related proteins. Oxytocin upregulated phosphorylated ERK1/2 and Bcl-2 while downregulating BAX and caspase-3, reducing the BAX/Bcl-2 ratio. Conclusions: Oxytocin effectively protects PC12 cells from Aβ-induced neurotoxicity, highlighting its potential as a therapeutic agent for AD. Further research is needed to clarify oxytocin's mechanisms and clinical implications in AD treatment.

RevDate: 2025-03-27

Pérez Aguilar RDC, Rodríguez Salgado T, Cruz-Miranda OL, et al (2025)

Huperzine A Production and Acetylcholinesterase Inhibition by Phlegmariurus taxifolius Cell Suspension Culture: A Comparative Study in Flasks and an Airlift Bioreactor.

Pharmaceuticals (Basel, Switzerland), 18(3): pii:ph18030383.

Background: The callus cultures from the fronds of the lycophyte Phlegmariurus taxifolius produce the huperzine A (HupA) alkaloid, which is used in Alzheimer's disease treatment. This study aimed to establish the growth kinetics and HupA production by the newly HupS21 cell line grown in 250 mL flasks and in a 2 L airlift bioreactor. Methods: Batch-type kinetics were carried out for 60 days in 250 mL flasks and for 20 days in a 2 L airlift bioreactor. Measurements of dry weight (DW), specific growth rate (μ), doubling time (dt), pH, carbohydrate consumption, and HupA quantification were performed. The acetylcholinesterase (AChE) inhibitory assay of the HupS21 alkaloidal extract was determined. Results: The 250 mL flasks kinetic reached a maximum cell growth of 8.17 g/L DW, with a μ of 0.045 day[-1] and a dt of 15.40 days. The maximum HupA production was of 2.03 μg/g DW at day 45. In the 2 L airlift reactor, a maximum growth of 16.70 g/L DW, a μ of 0.062 day[-1], a dt of 11.20 days, and HupA production of 2.48 μg/g DW at day 15 were obtained. The alkaloidal extract from the HupS21 cell line at 100 μg/mL showed an AChE inhibitory activity of 85.6 ± 1.27%. Conclusions: The airlift reactor outperformed the flask cultures in maximum cell growth, specific growth rate, doubling time, and HupA production. To our knowledge, this research is the first report on the establishment of suspension cell cultures of P. taxifolius in shaken flasks and in an airlift bioreactor, providing a foundation for scaling up HupA production for pharmaceutical use.

RevDate: 2025-03-27

Tsimpili H, G Zoidis (2025)

A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.

Pharmaceuticals (Basel, Switzerland), 18(3): pii:ph18030369.

The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into consideration muscarinic receptors and cholinesterase enzymes. Targeting a specific subtype of five primary muscarinic receptor subtypes (M1-M5) through agonism or antagonism may benefit patients; thus, there is a great pharmaceutical research interest. Inhibition of AChE and BChE, orthosteric or allosteric, or partial agonism of M1 mAChR are correlated with Alzheimer's disease (AD) symptoms improvement. Agonism or antagonism on different muscarinic receptor subunits may lessen schizophrenia symptoms (especially positive allosteric modulation of M4 mAChR). Selective antagonism of M4 mAChR is a promising treatment for Parkinson's disease and dystonia, and the adverse effects are limited compared to inhibition of all five mAChR. Additionally, selective M5 antagonism plays a role in drug independence behavior. M3 mAChR overexpression is associated with malignancies, and M3R antagonists seem to have a therapeutic potential in cancer, while M1R and M2R inhibition leads to reduction of neoangiogenesis. Depending on the type of cancer, agonism of mAChR may promote cancer cell proliferation (as M3R agonism does) or protection against further tumor development (M1R agonism). Thus, there is an intense need to discover new potent compounds with specific action on muscarinic receptor subtypes. Chemical structures, chemical modification of function groups aiming at action enhancement, reduction of adverse effects, and optimization of Drug Metabolism and Pharmacokinetics (DMPK) will be further discussed, as well as protein-ligand docking.

RevDate: 2025-03-27

Zou Y, Zhang J, Chen L, et al (2025)

Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.

Pharmaceutics, 17(3): pii:pharmaceutics17030388.

Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.

RevDate: 2025-03-27

Tew VK, Barathan M, Nordin F, et al (2025)

Emerging Role of Mesenchymal Stromal Cell and Exosome Therapies in Treating Cognitive Impairment.

Pharmaceutics, 17(3): pii:pharmaceutics17030284.

Cognitive aging, characterized by the gradual decline in cognitive functions such as memory, attention, and problem-solving, significantly impacts daily life. This decline is often accelerated by neurodegenerative diseases, particularly Alzheimer's Disease (AD) and Parkinson's Disease (PD). AD is marked by the accumulation of amyloid-beta plaques and tau tangles, whereas PD involves the degeneration of dopaminergic neurons. Both conditions lead to severe cognitive impairment, greatly diminishing the quality of life for affected individuals. Recent advancements in regenerative medicine have highlighted mesenchymal stromal cells (MSCs) and their derived exosomes as promising therapeutic options. MSCs possess regenerative, neuroprotective, and immunomodulatory properties, which can promote neurogenesis, reduce inflammation, and support neuronal health. Exosomes, nanosized vesicles derived from MSCs, provide an efficient means for delivering bioactive molecules across the blood-brain barrier, targeting the underlying pathologies of AD and PD. While these therapies hold great promise, challenges such as variability in MSC sources, optimal dosing, and effective delivery methods need to be addressed for clinical application. The development of robust protocols, along with rigorous clinical trials, is crucial for validating the safety and efficacy of MSC and exosome therapies. Future research should focus on overcoming these barriers, optimizing treatment strategies, and exploring the integration of MSC and exosome therapies with lifestyle interventions. By addressing these challenges, MSC- and exosome-based therapies could offer transformative solutions for improving outcomes and enhancing the quality of life for individuals affected by cognitive aging and neurodegenerative diseases.

RevDate: 2025-03-27

Lei K, Zhou L, Dan M, et al (2025)

Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting.

Pharmaceutics, 17(3): pii:pharmaceutics17030280.

Central nervous system (CNS) diseases, such as brain tumors, Alzheimer's disease, and Parkinson's disease, significantly impact patients' quality of life and impose substantial economic burdens on society. The blood-brain barrier (BBB) limits the effective delivery of most therapeutic drugs, especially natural products, despite their potential therapeutic effects. The Trojan Horse strategy, using nanotechnology to disguise drugs as "cargo", enables them to bypass the BBB, enhancing targeting and therapeutic efficacy. This review explores the applications of natural products in the treatment of CNS diseases, discusses the challenges posed by the BBB, and analyzes the advantages and limitations of the Trojan Horse strategy. Despite the existing technical challenges, future research is expected to enhance the application of natural drugs in CNS treatment by integrating nanotechnology, improving delivery mechanisms, and optimizing targeting characteristics.

RevDate: 2025-03-27

Sundararaman L, Gouda D, Kumar A, et al (2025)

Glucagon-like Peptide-1 Receptor Agonists: Exciting Avenues Beyond Weight Loss.

Journal of clinical medicine, 14(6): pii:jcm14061978.

The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer's disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Palacino F, Manganotti P, A Benussi (2025)

Targeting Neural Oscillations for Cognitive Enhancement in Alzheimer's Disease.

Medicina (Kaunas, Lithuania), 61(3): pii:medicina61030547.

Alzheimer's disease (AD), the most prevalent form of dementia, is marked by progressive cognitive decline, affecting memory, language, orientation, and behavior. Pathological hallmarks include extracellular amyloid plaques and intracellular tau tangles, which disrupt synaptic function and connectivity. Neural oscillations, the rhythmic synchronization of neuronal activity across frequency bands, are integral to cognitive processes but become dysregulated in AD, contributing to network dysfunction and memory impairments. Targeting these oscillations has emerged as a promising therapeutic strategy. Preclinical studies have demonstrated that specific frequency modulations can restore oscillatory balance, improve synaptic plasticity, and reduce amyloid and tau pathology. In animal models, interventions, such as gamma entrainment using sensory stimulation and transcranial alternating current stimulation (tACS), have shown efficacy in enhancing memory function and modulating neuroinflammatory responses. Clinical trials have reported promising cognitive improvements with repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS), particularly when targeting key hubs in memory-related networks, such as the default mode network (DMN) and frontal-parietal network. Moreover, gamma-tACS has been linked to increased cholinergic activity and enhanced network connectivity, which are correlated with improved cognitive outcomes in AD patients. Despite these advancements, challenges remain in optimizing stimulation parameters, individualizing treatment protocols, and understanding long-term effects. Emerging approaches, including transcranial pulse stimulation (TPS) and closed-loop adaptive neuromodulation, hold promise for refining therapeutic strategies. Integrating neuromodulation with pharmacological and lifestyle interventions may maximize cognitive benefits. Continued interdisciplinary efforts are essential to refine these approaches and translate them into clinical practice, advancing the potential for neural oscillation-based therapies in AD.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Singh AA, Khan F, M Song (2025)

Biofilm-Associated Amyloid Proteins Linked with the Progression of Neurodegenerative Diseases.

International journal of molecular sciences, 26(6): pii:ijms26062695.

Biofilm-associated amyloid proteins have emerged as significant contributors to the progression of neurodegenerative diseases, representing a complex intersection of microorganisms and human health. The cross-beta sheet structure characteristic of amyloids produced by gut-colonizing bacteria remains intact, crucial for the resilience of biofilms. These amyloids exacerbate neurodegenerative disorders such as Alzheimer's and Parkinson's by cross-seeding human amyloidogenic proteins like amyloid-beta and α-synuclein, accelerating their misfolding and aggregation. Despite molecular chaperones and heat shock proteins maintaining protein homeostasis, bacterial amyloids can overwhelm them, worsening neuronal damage. Genetic variations in chaperone genes further influence amyloidogenesis and neurodegeneration. Persistent bacterial infections and inflammation compromise the blood-brain barrier, allowing inflammatory molecules and amyloids to enter the brain, perpetuating the cycle of neurodegeneration. The gut-brain axis underscores the impact of dysbiosis and gut microbiota on brain function, potentially contributing to neurodegeneration. The enhancement of biofilm resilience and antibiotic resistance by functional amyloid fibrils complicates the treatment landscape. The interplay among chaperone systems, microbial amyloids, and neurodegenerative diseases underscores the urgent need for advanced treatment strategies targeting these pathways to attenuate disease progression. Understanding the processes that relate biofilm-associated amyloids to the onset of neurological disorders is critical for diagnosing and developing novel treatment strategies.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Muramoto S, Shimizu S, Shirakawa S, et al (2025)

Noradrenaline Synergistically Enhances Porphyromonas gingivalis LPS and OMV-Induced Interleukin-1β Production in BV-2 Microglia Through Differential Mechanisms.

International journal of molecular sciences, 26(6): pii:ijms26062660.

Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer's disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1β (IL-1β) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30-1000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1β up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 μg/mL) and OMVs (150 μg of protein/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the β2 adrenergic receptor (Aβ2R)-mediated pathway. NF-κB, which is activated by the Pg LPS/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1β production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-κB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-κB p65 to the IκB site, resulting in the synergistic augmentation of the IL-1β promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9/p52/RelB-mediated pathway. The Aβ2R/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1β in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1β in response to Pg LPS and OMVs through distinct mechanisms.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Fang X, Border JJ, Zhang H, et al (2025)

A Soluble Epoxide Hydrolase Inhibitor Improves Cerebrovascular Dysfunction, Neuroinflammation, Amyloid Burden, and Cognitive Impairments in the hAPP/PS1 TgF344-AD Rat Model of Alzheimer's Disease.

International journal of molecular sciences, 26(6): pii:ijms26062433.

Alzheimer's disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We recently reported that SNPs in soluble epoxide hydrolase (sEH) are linked to AD in human genetic studies and that long-term administration of an sEH inhibitor attenuated cerebral vascular and cognitive dysfunction in a rat model of AD. However, the mechanisms linking changes in cerebral vascular function and neuroprotective actions of sEH inhibitors in AD remain to be determined. This study investigated the effects of administration of an sEH inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood-brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP/PS1 TgF344-AD rat model of AD. We observed predominant β-amyloid accumulation in the brains of 9-10-month-old AD rats and that TPPU treatment for three months reduced amyloid burden. The functional hyperemic response to whisker stimulation was attenuated in AD rats, and TPPU normalized the response. The sEH inhibitor, TPPU, mitigated capillary rarefaction, BBB leakage, and activation of astrocytes and microglia in AD rats. TPPU increased the expression of pre- and post-synaptic proteins and reduced loss of hippocampal neurons and cognitive impairments in the AD rats, which was confirmed in a transcriptome and GO analysis. These results suggest that sEH inhibitors could be a novel therapeutic strategy for AD.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Wang K, Adjeroh DA, Fang W, et al (2025)

Comparison of Deep Learning and Traditional Machine Learning Models for Predicting Mild Cognitive Impairment Using Plasma Proteomic Biomarkers.

International journal of molecular sciences, 26(6): pii:ijms26062428.

Mild cognitive impairment (MCI) is a clinical condition characterized by a decline in cognitive ability and progression of cognitive impairment. It is often considered a transitional stage between normal aging and Alzheimer's disease (AD). This study aimed to compare deep learning (DL) and traditional machine learning (ML) methods in predicting MCI using plasma proteomic biomarkers. A total of 239 adults were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort along with a pool of 146 plasma proteomic biomarkers. We evaluated seven traditional ML models (support vector machines (SVMs), logistic regression (LR), naïve Bayes (NB), random forest (RF), k-nearest neighbor (KNN), gradient boosting machine (GBM), and extreme gradient boosting (XGBoost)) and six variations of a deep neural network (DNN) model-the DL model in the H2O package. Least Absolute Shrinkage and Selection Operator (LASSO) selected 35 proteomic biomarkers from the pool. Based on grid search, the DNN model with an activation function of "Rectifier With Dropout" with 2 layers and 32 of 35 selected proteomic biomarkers revealed the best model with the highest accuracy of 0.995 and an F1 Score of 0.996, while among seven traditional ML methods, XGBoost was the best with an accuracy of 0.986 and an F1 Score of 0.985. Several biomarkers were correlated with the APOE-ε4 genotype, polygenic hazard score (PHS), and three clinical cerebrospinal fluid biomarkers (Aβ42, tTau, and pTau). Bioinformatics analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed several molecular functions and pathways associated with the selected biomarkers, including cytokine-cytokine receptor interaction, cholesterol metabolism, and regulation of lipid localization. The results showed that the DL model may represent a promising tool in the prediction of MCI. These plasma proteomic biomarkers may help with early diagnosis, prognostic risk stratification, and early treatment interventions for individuals at risk for MCI.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Pilotto A, Carini M, Bresciani R, et al (2025)

Next Generation Sequencing Analysis in Patients Affected by Parkinson's Disease and Correlation Between Genotype and Phenotype in Selected Clinical Cases.

International journal of molecular sciences, 26(6): pii:ijms26062397.

Parkinson's Disease (PD) is the most frequent movement disorder and is second only to Alzheimer's Disease as the most frequent neurodegenerative pathology. Early onset Parkinson's disease (EOPD) is less common and may be characterized by genetic predisposition. NGS testing might be useful in the diagnostic assessment of these patients. A panel of eight genes (SNCA, PRKN, PINK1, DJ1, LRRK2, FBXO7, GBA1 and HFE) was validated and used as a diagnostic tool. A total of 38 in sequence EOPD patients of the Parkinson's Disease Unit of our Hospital Institution were tested. In addition, the number of the hexanucleotide repeats of the C9ORF72 gene and the frequency of main HFE mutations were evaluated. Six patients were carriers of likely pathogenic mutations in heterozygosity in the analyzed genes, one of them presented mutations in association and another had a complex genetic background. Their clinical symptoms were correlated with their genotypes. In the cohort of patients, only the p.Cys282Tyr of HFE was significantly decreased in the dominant model and allele contrast comparison. Only one patient with one allele of C9ORF72 containing 10 repeats was identified and clinically described. The clinical signs of sporadic and monogenic PD are often very similar; for this reason, it is fundamental to correlate genotypes and phenotypes, as we tried to describe here, to better classify PD patients with the aim to deepen our knowledge in the molecular mechanisms involved and collaborate in reaching a personalized management and treatment.

RevDate: 2025-03-27

Azarfar K, Decourt B, Sanchez Camacho B, et al (2025)

Cholesterol-modifying strategies for alzheimer disease: promise or fallacy?.

Expert review of neurotherapeutics [Epub ahead of print].

INTRODUCTION: As the world population ages, Alzheimer disease (AD) prevalence increases. However, understanding of AD etiology continues to evolve, and the pathophysiological processes involved are only partially elucidated. One compound suspected to play a role in the development and progression of AD is cholesterol. Several lines of evidence support this connection, yet it remains unclear whether cholesterol-modifying strategies have potential applications in the clinical management of AD.

AREAS COVERED: A deep literature search using PubMed was performed to prepare this narrative review. The literature search, performed in early 2024, was inclusive of literature from 1990 to 2024. After providing an overview of cholesterol metabolism, this study summarizes key preclinical studies that have investigated cholesterol-modifying therapies in laboratory models of AD. It also summarizes past and current clinical trials testing specific targets modulated by anti-cholesterol therapies in AD patients.

EXPERT OPINION: Based on current epidemiological and mechanistic studies, cholesterol likely plays a role in AD etiology. The use of cholesterol-modifying therapies could be a promising treatment approach if administered at presymptomatic to early AD phases, but it is unlikely to be efficient in mild, moderate, and late AD stages. Several recommendations are provided for hypercholesterolemia management in AD patients.

RevDate: 2025-03-27

Kalokhe VM, Simran S, Ahmad A, et al (2025)

Unveiling Gaps and Demographic Influences in Alzheimer's Therapy: A Data-Centric Study of FDA-Approved Late-Phase Clinical Trials.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology [Epub ahead of print].

BACKGROUND: Alzheimer's disease is more prevalent in women than in men. In this study, the author examined the U.S. Food and Drug Administration (FDA) completed phase 4 clinical trials associated with Alzheimer's. The research aims to evaluate the women's participation-to-prevalence ratio (PPR) for Alzheimer's disease.

METHOD: Using the FDA's publicly available clinical trial database, 45 Phase 4 Alzheimer's trials from 2003 to 2019 were assessed. Further, the total PPR and yearly PPR value are calculated by dividing the percentage of women in clinical trials by the total percentage of women affected by Alzheimer's disease. The PPR value equal to 1 showcases the balanced participation of females in the Phase 4 clinical trial and the diseased affected population.

RESULT: Out of 45 trials, 41 were completed and four were terminated. The gender data was unavailable for three trials. In 38 clinical trials associated with Alzheimer's disease, 4502 participants were enrolled. Among 4502, 2604 (57.84%) were found to be female and 1898 (42.15%) were male. The PPR for women was 0.80, reflecting an adequate representation of women participants in late-phase clinical trials. The yearly PPR reduction has been seen in female participants.

CONCLUSION: In the year-based PPR, the range was from 0.72-1.0. In the initial year, the range was 1, which was reduced to 0.72 in 2007. In total, 38 completed clinical trials, 18 trials used placebo treatment, and the gender ratio in placebo was adequate. More transparency is essential in gender concerning SAE in publicly available databases.

RevDate: 2025-03-26

Koyama G, Nakano M, Takata T, et al (2025)

Reversible dementia due to hyperthyroidism: Cognitive impairment, delusions, and agitation resolved with antithyroid treatment.

RevDate: 2025-03-26

Yu T, Wei Z, Wang J, et al (2025)

Ginkgo biloba Extract GBE50 ameliorates cerebrovascular dysfunction and cognitive impairment in a mouse model of Alzheimer's disease.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 141:156646 pii:S0944-7113(25)00286-7 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder in which neurovascular unit (NVU) dysfunction plays a critical role. GBE50, a refined extract of Ginkgo biloba containing over 50 % total flavonoids and terpene lactones, is widely used in the clinical prevention and treatment of cardiovascular and cerebrovascular diseases due to its anti-platelet aggregation, anti-inflammatory, and antioxidant properties. However, its specific effects on NVU integrity and cerebrovascular function in AD remain unclear.

PURPOSE: This study aims to investigate the therapeutic effects of GBE50 on NVU integrity and cognitive impairment in an AD mouse model.

METHODS: APP/PS1 transgenic mice were treated with GBE50 via intragastric administration for 10 weeks. Cognitive performance was assessed through behavioral tests, while the structural and functional integrity of the NVU was evaluated using immunofluorescence, laser speckle imaging, and in vivo multi-photon imaging. Furthermore, target prediction and transcriptomic analyses were conducted to uncover potential molecular mechanisms and identify specific targets of GBE50.

RESULTS: GBE50 treatment significantly alleviated cognitive deficits in APP/PS1 mice. It enhanced cerebrovascular structure and function by increasing vessel density, diameter, and branching, leading to improved cerebral blood flow (CBF). GBE50 also restored NVU components such as endothelial cells, astrocytes, and pericytes, promoted parenchyma and perivascular Aβ clearance, and reduced neuroinflammation. Bioinformatics and transcriptomic analyses revealed that GBE50 exerted its effects by regulating pathways related to vascular repair, neuroprotection, and Aβ clearance.

CONCLUSION: The findings demonstrate that GBE50 improves cognitive dysfunction in AD by restoring NVU integrity and cerebrovascular function through multi-target mechanisms. This study highlights the potential of GBE50 as a promising therapeutic approach for AD and other neurodegenerative diseases involved in cerebrovascular dysfunction.

RevDate: 2025-03-26

Walsh AE, JR Lukens (2025)

Harnessing microglia-based cell therapies for the treatment of neurodegenerative diseases.

Current opinion in immunology, 94:102552 pii:S0952-7915(25)00028-7 [Epub ahead of print].

Given the growing evidence linking microglia to the onset and progression of various neurodegenerative diseases, these brain-resident macrophages have emerged as a promising cell type for targeted therapeutic interventions. This review highlights recent studies that utilized innovative, microglia-focused strategies for the treatment of diverse neurodegenerative disorders including lysosomal storage disorders, granulin frontotemporal dementia, and Alzheimer's disease. Cutting-edge therapeutic strategies range from replacing faulty microglia with peripheral macrophage precursors or induced human pluripotent stem cell-derived microglia to engineering microglia that target toxic aggregates or deliver remediating payloads. We also examine the potential limitations as well as the clinical benefits of these strategies.

RevDate: 2025-03-26
CmpDate: 2025-03-26

Sillapakong P, Wakabayashi T, K Suzuki (2025)

Naturido alleviates amyloid β1-42-induced adverse effects in a transgenic Caenorhabditis elegans model of Alzheimer's disease.

PloS one, 20(3):e0320636 pii:PONE-D-24-54123.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily associated with aging. While the amyloid hypothesis is not the only explanation for AD pathogenesis, it is widely recognized that the accumulation of amyloid β (Aβ) protein triggers pathological changes in the brains of patients. In a previous study, we showed that Naturido, a cyclic peptide derived from the medicinal fungus (Isaria japonica) grown on domestic silkworms (Bombyx mori), could reverse several age-related deficits in senescence-accelerated mice. In this study, we explored the potential of Naturido to reduce Aβ-related toxicity in transgenic Caenorhabditis elegans models of AD, where human Aβ1-42 protein is overexpressed in neurons. Our results demonstrated that Naturido administration alleviated various phenotypes, including Aβ-induced impairment in associative learning, serotonin hypersensitivity, and locomotion in the transgenic C. elegans. These findings suggest the potential of Naturido as a candidate molecule for the prevention and/or treatment of AD.

RevDate: 2025-03-26
CmpDate: 2025-03-26

Liu H, Zhou J, WW Yang (2025)

Etomidate ameliorates Alzheimer-like neuropathology and cognitive impairment in APP/PS1 mice.

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 76(1):.

To investigate the effect and mechanism of etomidate on attenuating Alzheimer-like neuropathology and cognitive impairment in mice with Alzheimer's disease (AD). AD was modeled in vivo using amyloid precursor protein/presenilin 1 (APP/PS1) mice. After etomidate treatment, behavioral experiments and histopathological observation of hippocampus were performed. Hippocampal Aβ deposition was detected using immunofluorescence. AD was modeled in vitro using a HT22 cells which are an immortalized cell line derived from primary mouse hippocampal neurons induced by Aβ1-42. Cell viability, apoptosis rate and LDH release were detected after etomidate intervention. Synaptic proteins were detected by mmunofluorescence or Western blot, and neurotransmitters and inflammatory factors were detected by ELISA. Etomidate improved the memory ability, novel object cognition ability, and spatial learning of APP/PS1 mice. The improvement of cognitive function and memory ability may be due to the recovery effect of etomidate on hippocampal pathological changes in APP/PS1 mice, including reducing Aβ deposition, neuron and synaptic loss. Etomidate also regulated neuroinflammation and the release of neurotransmitters GABA and 5-HT in APP/PS1 mice. Etomidate effectively reversed Aβ1-42-induced hippocampal neuronal damage, which was reflected in the improvement of cell viability and the inhibition of cytotoxicity, apoptosis and pro-inflammatory factors. Etomidate reversed the inhibition of the expression of synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) induced by Aβ1-42 in vitro. After etomidate intervention, the expression of serotonin 1A receptor (5HT1A) and gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) in Aβ1-42-injured HT22 cells were up-regulated, and free calcium ion was increased. In conclusion, etomidate ameliorates Alzheimer-like neuropathology and cognitive impairment in APP/PS1 mice, indicating that etomidate may be a potentially useful drug for the treatment of AD.

RevDate: 2025-03-26

Ene M, Savuca A, Ciobica AS, et al (2025)

The Neurobehavioral Impact of Zinc Chloride Exposure in Zebrafish: Evaluating Cognitive Deficits and Probiotic Modulation.

Toxics, 13(3): pii:toxics13030193.

Zinc contamination in aquatic environments has become a growing concern due to its potential to bioaccumulate and induce neurotoxic effects in aquatic organisms. As an essential trace element, zinc plays a crucial role in various physiological processes, but excessive exposure can disrupt the gut-brain axis, leading to cognitive and behavioral impairments. Recent studies have suggested that probiotics may offer protective effects against environmental neurotoxins by modulating the gut microbiota and associated neurological functions. The zebrafish (Danio rerio) has emerged as a valuable model organism for studying the biological mechanisms underlying neurotoxicity and potential therapeutic interventions. This study aimed to assess the effects of probiotics on cognitive impairments induced by zinc chloride (ZnCl2) exposure in zebrafish. Specifically, zebrafish were exposed to ZnCl2 at concentrations of 0.5 mg/L and 1.0 mg/L for 96 h, followed by a 7-day post-exposure period to probiotics (Bifidobacterium longum, Bifidobacterium animalis lactis, Lactobacillus rhamnosus). ZnCl2 exposure at these concentrations is already known to induce behavioral and neuromotor deficits resembling Alzheimer's disease-like symptoms in zebrafish models, making it a suitable model for evaluating the neuroprotective potential of probiotics. Behavioral assessments including sociability tests along with short- and long-term memory evaluations were conducted using EthoVision XT 16 software. Memory tests demonstrated that ZnCl2 exposure impaired cognitive functions, while probiotic treatment did not significantly ameliorate these deficits. In the social behavior test, ZnCl2 at 0.5 mg/L resulted in a marked decrease in sociability, whereas exposure to 1.0 mg/L did not induce significant changes. However, post-exposure probiotic administration following ZnCl2 intoxication at 1.0 mg/L exhibited an anxiolytic effect on zebrafish. These findings suggest that probiotics may exhibit partial neurobehavioral benefits following zinc chloride-induced toxicity, particularly in mitigating anxiety-like behaviors rather than cognitive deficits. Further investigations are needed to elucidate the precise mechanisms by which probiotics interact with the gut-brain axis in the context of heavy metal neurotoxicity.

RevDate: 2025-03-27

Yang Y, Huh K, YT Kwak (2025)

The Influence of a Specialized Dementia Ward on the Treatment of Alzheimer's Disease Patients.

Journal of personalized medicine, 15(3):.

Background: Hospitalization for severe neuropsychiatric symptoms in Alzheimer's disease (AD) presents challenges, often requiring environments that ensure safety while addressing therapeutic needs. Traditional closed wards, originally designed for psychiatric conditions like schizophrenia, may not fully address the unique needs of AD patients. This study evaluates the effectiveness of a Specialized Dementia Ward (SDW) tailored for AD patients compared to a General Ward (GW). Methods: A retrospective study compared 51 AD patients in an SDW (February 2018-January 2019) and 40 AD patients in a GW (December 2017-January 2018). Patients met NINCDS-ADRDA criteria, with a Clinical Dementia Rating (CDR) ≤ 2 and a Korean Mini-Mental State Examination (K-MMSE) ≤ 20. Clinical assessments at admission and four weeks included K-MMSE, Resident Assessment Instrument Minimum Data Set Version 2.0 (RAI-MDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Psychotropic medication use, length of stay, and discharge destination were also analyzed. Results: No statistically significant differences emerged between SDW and GW groups regarding baseline demographics, cognitive function, ADL, or neuropsychiatric symptoms. At four weeks, both groups exhibited trends toward improved K-MMSE, RAI-MDS, and NPI-Q scores and reduced psychotropic usage, but these did not reach statistical significance. Although mean length of stay was shorter for SDW patients (3.2 vs. 4.9 months; p = 0.078), the difference was not significant. Notably, a significantly higher proportion of SDW patients were discharged home (58.8% vs. 37.5%; p = 0.049). Conclusions: Although clinical outcomes were comparable, the SDW demonstrated advantages in facilitating discharge to home, suggesting that tailored ward environments may better support AD patients. These findings underscore the importance of therapeutic environments in dementia care and highlight the need for further research on specialized dementia ward designs to improve outcomes and patient satisfaction.

RevDate: 2025-03-27
CmpDate: 2025-03-26

Jia C, Chai J, Zhang S, et al (2025)

The Advancements of Marine Natural Products in the Treatment of Alzheimer's Disease: A Study Based on Cell and Animal Experiments.

Marine drugs, 23(3):.

As life expectancy rises and the aging population grows, Alzheimer's disease (AD) has become a significant global health concern. AD is a complex neurodegenerative disorder with an unclear etiology. Current hypotheses primarily focus on β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, and neuroinflammation as key pathological processes. Given the limited efficacy of existing therapeutic strategies, there is an urgent need to explore novel treatment options. Marine natural products have garnered significant attention due to their unique chemical structures and diverse bioactivities, demonstrating potential for multi-target interventions in AD. This review systematically summarizes the roles of marine-derived compounds, including polysaccharides, carotenoids, and polyphenols, in modulating Aβ aggregation, mitigating tau protein pathology, and regulating gut-brain axis dysfunction. Furthermore, the challenges of current research are discussed, with an emphasis on improving blood-brain barrier permeability and optimizing drug delivery systems to facilitate clinical translation.

RevDate: 2025-03-27

Stella R, Bertoli A, Lopreiato R, et al (2025)

A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.

Journal of fungi (Basel, Switzerland), 11(3):.

TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.

RevDate: 2025-03-27

Shen X, Feng R, Zhou R, et al (2025)

Ceramide as a Promising Tool for Diagnosis and Treatment of Clinical Diseases: A Review of Recent Advances.

Metabolites, 15(3):.

Background/Objectives: Ceramide, a sphingolipid metabolite, has emerged as a key player in various physiological and pathological processes. Changes in ceramide levels are associated with the occurrence and development of various diseases, highlighting its potential as a biomarker of various clinical diseases. Methods: The biosynthesis and metabolism of ceramide are discussed, along with its functions in cell signaling, apoptosis, and inflammation. This study further examines the potential of ceramide as a biomarker for disease diagnosis and treatment. Results: This article highlights the involvement of ceramide in several diseases, including cardiovascular diseases, dermatosis, cancer, neurodegenerative disorders and metabolic syndromes. For each disease, the potential of ceramide as a biomarker for disease diagnosis and prognosis is explored, and the feasibility of therapeutic strategies targeting ceramide metabolism are reviewed. Additionally, the challenges and future directions in the field of ceramide research are addressed. Conclusions: This review article provides an overview of the recent advances in understanding the role of ceramide in clinical diseases and its potential as a diagnostic and therapeutic tool.

RevDate: 2025-03-27

Ceccarelli Ceccarelli D, SB Solerte (2025)

Unravelling Shared Pathways Linking Metabolic Syndrome, Mild Cognitive Impairment, Dementia, and Sarcopenia.

Metabolites, 15(3):.

Background: Aging is characterized by shared cellular and molecular processes, and aging-related diseases might co-exist in a cluster of comorbidities, particularly in vulnerable individuals whose phenotype meets the criteria for frailty. Whilst the multidimensional definition of frailty is still controversial, there is an increasing understanding of the common pathways linking metabolic syndrome, cognitive decline, and sarcopenia, frequent conditions in frail elderly patients. Methods: We performed a systematic search in the electronic databases Cochrane Library and PubMed and included preclinical studies, cohort and observational studies, and trials. Discussion: Metabolic syndrome markers, such as insulin resistance and the triglyceride/HDL C ratio, correlate with early cognitive impairment. Insulin resistance is a cause of synaptic dysfunction and neurodegeneration. Conversely, fasting and fasting-mimicking agents promote neuronal resilience by enhancing mitochondrial efficiency, autophagy, and neurogenesis. Proteins acting as cellular metabolic sensors, such as SIRT1, play a pivotal role in aging, neuroprotection, and metabolic health. In AD, β-amyloid accumulation and hyperphosphorylated tau in neurofibrillary tangles can cause metabolic reprogramming in brain cells, shifting from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect in cancer. The interrelation of metabolic syndrome, sarcopenia, and cognitive decline suggests that targeting these shared metabolic pathways could mitigate all the conditions. Pharmacological interventions, including GLP-1 receptor agonists, metformin, and SIRT 1 inducers, demonstrated neuroprotective effects in animals and some preliminary clinical models. Conclusions: These findings encourage further research on the prevention and treatment of neurodegenerative diseases as well as the drug-repurposing potential of molecules currently approved for diabetes, dyslipidemia, and metabolic syndrome.

RevDate: 2025-03-26

Harding CD, Holloway BM, DeYoung PN, et al (2025)

Subjective daytime sleepiness, not sleep quality or hypoxia, predicts sleep-dependent memory consolidation in a cohort of older adults.

Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine [Epub ahead of print].

STUDY OBJECTIVES: Aging markedly increases the risk of both Alzheimer's disease (AD) and obstructive sleep apnea (OSA). Memory deficits, an early indicator of AD, can be reduced in middle-aged OSA sufferers through treatment, with positive-airway pressure being the first line treatment standard. Here, we utilize natural variation in the OSA severity of an older-aged cohort to investigate whether hypoxia or sleep quality predict sleep-dependent memory consolidation (SDMC).

METHODS: Participants aged 65-85 years not currently receiving OSA treatment were recruited from the San Diego community via advertisement and referrals from other sleep studies. Participants undertook a computerized neurocognitive battery and overnight polysomnography. SDMC was measured using a word-pair associates task. Two linear regression analyses assessed associations between 1) SDMC and hypoxia metrics and 2) SDMC and sleep quality metrics.

RESULTS: The study included 67 participants (36 women, 31 men) most of whom presented with moderate or severe OSA. No significant associations were present in the hypoxia model. A negative association between Epworth Sleepiness Scale (ESS) score and SDMC was the only significant relationship in the sleep quality model. There was also a mild univariate correlation between ESS score and a second daytime function measure; the psychomotor vigilance task.

CONCLUSIONS: Objective measures of OSA pathology including hypoxia and sleep fragmentation were not associated with memory however ESS score, a subjective measure of daytime sleepiness, was associated with poorer memory task performance. This highlights the importance of considering subjective perceptions of sleep quality and daytime function in cognitive health outcomes of patients with OSA, particularly in older adults where they may integrate the myriad comorbidities that contribute to memory deficits in this group.

CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Identifier: NCT05094271; Title: Is Obstructive Sleep Apnea Important in the Development of Alzheimer's Disease?; URL: https://clinicaltrials.gov/study/NCT05094271.

RevDate: 2025-03-26

Ogunyemi OM, Macaulay OS, Gyebi GA, et al (2025)

Binding interaction of acetylcholinesterase with steroidal pregnanes: insight from machine learning and atomistic simulation.

Journal of biomolecular structure & dynamics [Epub ahead of print].

Acetylcholinesterase (AChE) inhibition is a key strategy in the treatment of Alzheimer's disease and other neurodegenerative disorders. While pregnane-based compounds have been suggested as AChE inhibitors, their mechanism of action remains unclear. This study employed machine learning (ML) and molecular modeling to probe the molecular interaction of AChE with steroidal pregnanes. The ML models were trained and validated on AChE bioactivity datasets to predict pIC50 and pKi values of small-molecule compounds. Among the models tested, the Random Forest Regressor demonstrated superior performance and was used to identify pregnanes with pIC50 ≥ 5 and pKi ≥ 7 as promising inhibitors. Molecular docking revealed strong molecular interactions between AChE and several pregnanes, particularly 21-[(3-Hydroxy-2-naphthyl)oxy]pregnane-2-one. This compound interacted with critical sub-sites within the AChE binding gorge, including the catalytic active site, peripheral anionic site, oxyanion hole, and anionic sub-site, through multiple hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations over 100 ns indicated structural stability and conformational flexibility of representative AChE-pregnane complexes as indicated by the dynamic parameters and cluster patterns. The Molecular Mechanics with Generalized Born Surface Area free energy analysis confirmed strong binding affinities, while residual energy decomposition provided insights into key residue contributions. Additionally, the pregnanes demonstrated favorable blood-brain barrier permeability and other drug-like properties, suggesting their potential as neurotherapeutic agents. Given their predicted bioactivity, strong interactions with AChE, and drug-like properties, the identified pregnanes warrant further optimization and experimental evaluation for the development of safe and effective AChE inhibitors.

RevDate: 2025-03-27
CmpDate: 2025-03-26

Qin G, Song R, Sun J, et al (2025)

Unveiling the Therapeutic Potential of Banxia Xiexin Decoction in Alzheimer's Disease: Insights From Network Pharmacology and Experimental Validation.

Drug design, development and therapy, 19:2133-2155.

BACKGROUND: Alzheimer's disease (AD) is associated with various pathological states for which there is no effective treatment. First documented in the Eastern Han Dynasty's medical classic, "Treatise on Febrile and Miscellaneous Diseases" (200-210 Anno Domini), Banxia Xiexin Decoction (BXD) stands as a quintessential approach to treating spleen ailments. Recent studies have shown BXD's effectiveness in mitigating memory impairment associated with AD. Yet, the precise mechanisms underlying BXD's action against AD require further exploration.

AIM OF THE STUDY: To explore the important components of BXD in exerting anti-AD effects and the underlying molecular mechanisms using network pharmacology, metabolomics analysis, and in vitro and in vivo validation strategies. Initially, candidates for BXD's application in AD therapy were identified through extensive database searches, followed by an analysis of protein-protein interactions (PPI). To elucidate BXD's therapeutic pathways in AD, we engaged in Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) assessments. Further, we delved into BXD's primary constituents through ultra-high-pressure liquid chromatography coupled with Q Exactive mass spectrometry and molecular docking techniques. Finally, AD-associated Aβ42-SY5Y cells and APPswe/PS1dE9 (APP/PS1) transgenic mice models were utilized to further determine the activity and mechanisms of BXD through various molecular or phenotypic assays and metabolomics analysis.

RESULTS: Our findings identified the PI3K/Akt signaling pathways as central to BXD's effects. Using in vitro and in vivo models, we found the activity of BXD against AD to be mediated by the suppression of neuroinflammation and apoptosis, accompanied by activation of the PI3K/Akt pathway. Finally, we observed robust changes in metabolite levels in the plasma of BXD-treated APP/PS1 mice.

CONCLUSION: Through systematic data analysis and experimental validation, the therapeutic advantages and fundamental molecular mechanisms of BXD in treating AD were revealed. These findings underscore the promising prospects and compelling potential of BXD, which targets the PI3K/Akt signaling pathway and inflammation, apoptosis, as a therapeutic strategy for improving AD.

RevDate: 2025-03-27

Simon C, Graves OK, Akeju O, et al (2025)

Elevated TDP-43 serum levels associated with postoperative delirium following major cardiac surgery.

Brain, behavior, & immunity - health, 45:100974.

BACKGROUND: Postoperative delirium is a recurring complication among vulnerable patients undergoing major cardiac surgery. While delirium has been associated with prodromal dementia, there is minimal evidence to support the causality of this nuanced relationship. Clarification as to how postoperative delirium might lead to neurodegenerative dementias, perhaps through evidence of contemporaneous biomarkers, would heighten the plausibility of a causal correlation. TAR DNA-binding protein 43 (TDP-43), a nuclear protein essential for transcriptional events, has been linked to pathological aggregation in Alzheimer's disease (AD) and AD-related dementias (ADRD).

METHODS: Circulating TDP-43 levels in cardiac surgical patients aged 60 years and older were evaluated in a biobank derived from the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) clinical trial. Serum total TDP-43 levels, measured with a single molecule array (Simoa), were compared across preoperative and postoperative day one timepoints according to delirium status assessed using the Confusion Assessment Method (CAM). To investigate the temporal changes in serum TDP-43, an independent validation cohort of 25 patients aged 60 years and older undergoing major cardiac surgery was analyzed.

RESULTS: Total serum TDP-43 levels increased by 16.5% (95% CI: 5.9%-27.9%, p = 0.0021) on postoperative day one compared to baseline levels. This increase was more pronounced in patients who experienced delirium (median increase of 55.1%, 95% CI: 22.9%-96.4%, p = 0.0002). Further, these findings were conserved in multiple logistic regression models adjusting for treatment, age, sex, and baseline cognitive scores. In the validation cohort, TDP-43 levels were found to be significantly elevated immediately following cardiopulmonary bypass from the baseline, with a gradual decrease by postoperative day one.

CONCLUSIONS: Our findings demonstrate that post-cardiac surgery delirium among vulnerable patients is associated with significant elevations in circulating TDP-43. This relationship suggests that TDP-43 may serve as a prognostic biomarker for acute neurological insults and blood-brain barrier integrity following cardiac surgery. Overall, our results provide mechanistic insights into the inter-relationship between postoperative delirium and subsequent cognitive impairment, potentially offering new avenues for early intervention in at-risk surgical patients.

RevDate: 2025-03-27

Doğancı O, M Sertel (2025)

Determination of balance, fall risk, and kinesiophobia in individuals with Alzheimer's Dementia.

Frontiers in psychology, 16:1535440.

OBJECTIVE: This study aimed to determine balance, fall risk, and kinesiophobia in individuals with Alzheimer's Dementia (AD).

METHODS: The study was completed with 18 AD and 18 healthy AD-free control group with early or moderate-stage AD diagnosed by a neurologist. Socio-demographic characteristics of the individuals were assessed using an evaluation form, and their balance was evaluated using the Tinetti Balance and Gait Assessment Test, Timed Up and Go Test, and Single Leg Standing Test. The Falls Risk Self-Assessment Scale (FRSAS) was used to assess the risk of falls. Kinesiophobia was assessed using the Tampa Scale for Kinesiophobia (TKS). Additionally, participants underwent the Mini-Mental State Examination (MMSE).

RESULT: The mean age of individuals with AD was lower than that of healthy individuals, with means of 69 ± 3.66 years and 65.4 ± 4.10 years, respectively (p = 0.012). The Tinetti balance (p = 0.005), Tinetti gait (p < 0.001), Tinetti total (p < 0.001), and the Mini-Mental State Examination (MMSE) (p < 0,001) scores were lower in AD individuals relative to controls. The FRSAS (p < 0.001) scores were higher in AD individuals relative to controls. The TKS scores were found to be similar between individuals with AD and the control group (p = 0.860).

CONCLUSION: It was found that individuals with Alzheimer's disease (AD) have poorer balance and a higher risk of falls compared to healthy individuals. In light of these results, balance assessments should be included when developing rehabilitation protocols for individuals with AD. Treatment protocols designed for this patient group must incorporate balance-specific exercise and training programs. Additionally, individual and environmental preventive measures should be implemented to reduce the risk of falls in individuals with AD.

CLINICAL TRIAL REGISTRATION: Clinical Trial Number: NCT05201768.

RevDate: 2025-03-27
CmpDate: 2025-03-26

Sun H, Hao Y, Liu H, et al (2025)

The immunomodulatory effects of GLP-1 receptor agonists in neurogenerative diseases and ischemic stroke treatment.

Frontiers in immunology, 16:1525623.

Glucagon-like peptide-1 (GLP-1) receptor is widely distributed in the digestive system, cardiovascular system, adipose tissue and central nervous system. Numerous GLP-1 receptor-targeting drugs have been investigated in clinical studies for various indications, including type 2 diabetes and obesity (accounts for 70% of the total studies), non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease. This review presented fundamental information regarding two categories of GLP-1 receptor agonists (GLP-1RAs): peptide-based and small molecule compounds, and elaborated their potential neuroprotective effects by inhibiting neuroinflammation, reducing neuronal apoptosis, and ultimately improving cognitive function in various neurodegenerative diseases. As a new hypoglycemic drug, GLP-1RA has a unique role in reducing the concurrent risk of stroke in T2D patients. Given the infiltration of various peripheral immune cells into brain tissue, particularly in the areas surrounding the infarct lesion, we further investigated the potential immune regulatory mechanisms. GLP-1RA could not only facilitate the M2 polarization of microglia through both direct and indirect pathways, but also modulate the quantity and function of T cell subtypes, including CD4, CD8, and regulatory T cells, resulting into the inhibition of inflammatory responses and the promotion of neuronal regeneration through interleukin-10 secretion. Therefore, we believe that the "Tregs-microglia-neuron/neural precursor cells" axis is instrumental in mediating immune suppression and neuroprotection in the context of ischemic stroke. Given the benefits of rapid diffusion, favorable blood-brain barrier permeability and versatile administration routes, these small molecule compounds will be one of the important candidates of GLP-1RA. We look forward to the further clinical evidence of small molecule GLP-1RA intervention in ischemic stroke or T2D complicated by ischemic stroke.

RevDate: 2025-03-26
CmpDate: 2025-03-26

Nam Y, Shin SJ, Kumar V, et al (2025)

Dual modulation of amyloid beta and tau aggregation and dissociation in Alzheimer's disease: a comprehensive review of the characteristics and therapeutic strategies.

Translational neurodegeneration, 14(1):15.

Alzheimer's disease (AD) is not a single-cause disease; rather, it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors. Aggregation and accumulation of amyloid beta (Aβ) and tau are the most prominent features in the brains of AD patients. Aggregated Aβ and tau exert neurotoxic effects in the central nervous system, contributing to the pathogenesis and progression of AD. They also act synergistically to cause neurodegeneration, resulting in memory loss. In this context, dual inhibition of Aβ and tau aggregation, or dissociation of these two aggregates, is considered promising for AD treatment. Recently, dual inhibitors capable of simultaneously targeting the aggregation and dissociation of both Aβ and tau have been investigated. Specific amino acid domains of Aβ and tau associated with their aggregation/dissociation have been identified. Subsequently, therapeutic agents that prevent aggregation or promote disaggregation by targeting these domains have been identified/developed. In this review, we summarize the major domains and properties involved in Aβ and tau aggregation, as well as the therapeutic effects and mechanisms of agents that simultaneously regulate their aggregation and dissociation. This comprehensive review may contribute to the design and discovery of next-generation dual-targeting drugs for Aβ and tau, potentially leading to the development of more effective therapeutic strategies for AD.

RevDate: 2025-03-26

Zhou Q, Wang W, C Deng (2025)

Advancements in Proteolysis Targeting Chimeras for Targeted Therapeutic Strategies in Alzheimer's Disease.

Molecular neurobiology [Epub ahead of print].

The presence of hyperphosphorylated Tau proteins, which mislocalize and form neurofibrillary tangles, and the accumulation of amyloid-β plaques are hallmark features of Alzheimer's disease (AD). These toxic protein aggregates contribute to synaptic impairment and neuronal dysfunction, underscoring the need for strategies aimed at effectively clearing or reducing these aggregates in the treatment of AD. In recent years, proteolysis targeting chimera (PROTAC) technology has emerged as a promising approach for selectively degrading dysfunctional proteins rather than merely inhibiting their function. This approach holds great potential for developing more effective interventions that could slow AD progression and improve patient outcomes. In this review, we first examine the pathological mechanisms underlying AD, focusing on abnormal protein degradation and accumulation. We then explore the evolution of PROTAC technology, its mechanisms of action, and the current status of drug development. Finally, we discuss the latest findings regarding the application of PROTACs in AD therapy, highlighting the potential benefits and limitations of this technology. Although promising, further clinical research is necessary to fully assess the safety and efficacy of PROTAC-based therapies for AD treatment.

RevDate: 2025-03-26
CmpDate: 2025-03-26

Burns AP, Fortel I, Zhan L, et al (2025)

Longitudinal excitation-inhibition balance altered by sex and APOE-ε4.

Communications biology, 8(1):488.

Neuronal hyperexcitation affects memory and neural processing across the Alzheimer's disease (AD) cognitive continuum. Levetiracetam, an antiepileptic, shows promise in improving cognitive impairment by restoring the neural excitation/inhibition balance in AD patients. We previously identified a hyper-excitable phenotype in cognitively unimpaired female APOE-ε4 carriers relative to male counterparts cross-sectionally. This sex difference lacks longitudinal validation; however, clarifying the vulnerability of female ε4-carriers could better inform antiepileptic treatment efficacy. Here, we investigated this sex-by-ε4 interaction using a longitudinal design. We used resting-state fMRI and diffusion tensor imaging collected longitudinally from 106 participants who were cognitively unimpaired for at least one scan event but may have been assessed to have clinical dementia ratings corresponding to early mild cognitive impairment over time. By including scan events where participants transitioned to mild cognitive impairment, we modeled the trajectory of the whole-brain excitation-inhibition ratio throughout the preclinical cognitively healthy continuum and extended to early impairment. A linear mixed model revealed a significant three-way interaction among sex, ε4-status, and time, with female ε4-carriers showing a significant hyper-excitable trajectory. These findings suggest a possible pathway for preventative therapy targeting preclinical hyperexcitation in female ε4-carriers.

RevDate: 2025-03-26
CmpDate: 2025-03-26

Tang H, Andrikopoulos N, Li Y, et al (2025)

Emerging biophysical origins and pathogenic implications of amyloid oligomers.

Nature communications, 16(1):2937.

The amyloid hypothesis has been a leading narrative concerning the pathophysiological foundation of Alzheimer's and Parkinson's disease. At the two ends of the hypothesis lie the functional protein monomers and the pathology-defining amyloid fibrils, while the early stages of protein aggregation are populated by polymorphic, transient and neurotoxic oligomers. As the structure and activity of oligomers are intertwined, here we show oligomers arising from liquid-liquid phase separation and β-barrel formation, their routes to neurodegeneration, and their role in cerebrovascular perturbation. Together, this Perspective converges on the multifaceted oligomer-axis central to the pathological origin and, hence, the treatment of amyloid diseases.

RevDate: 2025-03-25
CmpDate: 2025-03-26

Gutiérrez-Jiménez E, Rasmussen PM, Mikkelsen IK, et al (2025)

Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(3):e70023.

INTRODUCTION: Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes.

METHODS: We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax (Tg-SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances.

RESULTS: Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9- to 10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load.

DISCUSSION: These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD.

HIGHLIGHTS: Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model. Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD. Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.

RevDate: 2025-03-25
CmpDate: 2025-03-25

Guo LL, Zhang C, Huang YJ, et al (2025)

[Effects of nicotine exposure on endogenous metabolites in mouse brain based on metabolomics and mass spectrometry imaging].

Se pu = Chinese journal of chromatography, 43(4):363-371.

Nicotine, the principal alkaloid in tobacco, exhibits significant central nervous system activity and induces a wide array of physiological effects. In addition to its well-documented role in tobacco dependence, previous studies have suggested that nicotine also has diverse pharmacological properties. These include alleviating symptoms associated with Parkinson's disease, potentially reducing the risk of Alzheimer's disease, mitigating oxidative stress, as well as anti-inflammatory and anxiolytic effects. Neuroscientists frequently use an array of molecular biology techniques to elucidate the mechanisms responsible for the effects of nicotine on the central nervous system. However, disease onset is invariably accompanied by metabolic dysfunction, and organisms often exhibit complex and unpredictable responses to pharmacological stimuli. As a bioactive alkaloid with potent pharmacological properties, nicotine is able to cross the blood-brain barrier and induce brain-compound changes, which serves as the basis for its effects on the central nervous system. Consequently, examining the extensive impact of nicotine exposure on endogenous metabolites and metabolic pathways in the brain is an indispensable step toward providing a more robust foundation for understanding the complex physiological effects of nicotine. In this study, an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) metabolomic-analysis method was established to systematically examine the effects of repeated nicotine exposure on endogenous metabolites in mouse brains. Two chromatographic systems fitted with Acquity UPLC BEH HILIC (150 mm×2.1 mm, 1.7 μm) and BEH C18 (150 mm×2.1 mm, 1.7 μm) columns were used to determine the nicotine present in samples. As a result, the established UHPLC-MS/MS method identified a total of 759 endogenous metabolites. Compared with the saline group, nicotine exposure resulted in 575 significantly different metabolites, with 434 metabolites down-regulated and 141 up-regulated. Further pathway-enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that nicotine exposure primarily affects essential-amino-acid, lipid, nucleotide, carbohydrate, cofactor, and vitamin metabolism, as well as other amino-acid metabolic pathways in the brain. Although non-targeted metabolomics can simultaneously detect and analyze all small-molecule metabolites in an unbiased manner, accurately capturing metabolite changes in specific brain regions is challenging when dealing with complex brain-tissue systems. Targeting the aggregation of material bases and the delivery of precision treatment to certain brain regions is expected to be significant for the targeted therapy of central nervous system diseases. Airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was further used to directly visualize the nicotine-induced distributions and variations of differentially expressed metabolites in various brain regions, which revealed that nicotine exposure leads to the significant downregulation of choline, serine, aspartate, and malate levels throughout the brain. Specifically, taurine, acetylcholine, and adenosine levels were notably affected in the cortical, hippocampal, and striatal regions, respectively. Essential-amino-acid metabolism was most affected by nicotine, with lipid metabolism found to be the next-most affected pathway. These metabolic pathways predominantly affected the cortical region, whereas the striatum, hippocampus, thalamus, and cerebellum were affected to varying degrees. These findings provide novel experimental evidence that enhances our understanding of metabolic biomarkers associated with nicotine exposure.

RevDate: 2025-03-25

Bakhdil N (2025)

A kinetic theory approach for modeling Alzheimer's disease: Insights and challenges: Comment on "Mathematical models on Alzheimer's disease and its treatment: A review" by M. Maji and S. Khajanchi.

Physics of life reviews, 53:221-222 pii:S1571-0645(25)00049-1 [Epub ahead of print].

RevDate: 2025-03-25

Liu W, Chen X, Yang C, et al (2025)

Preventive effects of xanthohumol in APP/PS1 mice based on multi-omics atlas.

Brain research bulletin pii:S0361-9230(25)00128-5 [Epub ahead of print].

Alzheimer's disease (AD) is a complex disease with unknown etiology and pathogenesis. We described a combined analysis of murine proteomics and microbiomics to find potential therapeutic targets of different doses of xanthohumol (Xn), with the goal of providing a biological basis for the treatment of early AD. Xn improved the spatial learning and memory ability of APP/PS1 mice; this was associated with an increased number of newborn neurons in the subgranular zone (SGZ) and dentate gyrus (DG) and a decreased inflammatory response. 108 proteins were significantly changed after 0.5mg/kg Xn treatment while only 72 proteins changed by 5mg/kg Xn. Eight significant microbiota were modulated by different doses of Xn at line discriminant analysis (LDA) score 3.0, but only three of which were regulated by 0.5mg/kg Xn at LDA score 4.0. In addition, Xn treatment could significantly regulate the pathways of neurodegeneration- multiple diseases in the hippocampus and the penicillin and cephalosporin biosynthesis and atrazine degradation pathways in the gut. Interestingly, Nefl protein validated by correlation analysis was found in the common signaling pathway. 0.5mg/kg Xn was able to reverse the correlation between hippocampal proteins and gut microbiota. Xn treatment significantly improved cognitive function in AD transgenic mice. Different doses of Xn caused significant differences in protein expression and flora composition and abundance, suggesting that the doses of Xn should be selected with caution, and low dose may be better in the prevention of AD.

RevDate: 2025-03-27

Kazemi M, Sanati M, Shekari Khaniani M, et al (2025)

A review on the lncRNA-miRNA-mRNA regulatory networks involved in inflammatory processes in Alzheimer's disease.

Brain research, 1856:149595 pii:S0006-8993(25)00154-4 [Epub ahead of print].

Alzheimer's disease is a progressive neurodegenerative condition that is the most frequent reason for dementia. Due to the increasing trend of aging in societies, it will place a large social and financial burden on society. Although beta amyloid plaques and the formation of neurofibrillary tangles are mentioned as the main events in this disorder, the exact molecular pathology and inflammatory regulatory networks involved in neuroinflammatory events, as a fundamental pathogenic mechanism remain unknown. Understanding these molecular network pathways in addition to helping to understand the pathogenesis of Alzheimer's disease, can also help in the early diagnosis as well as the control of inflammatory processes that are involved in its progression. So, in this study, we intend to have an overview on the regulatory lncRNAs of Alzheimer's disease and their related miRNA and mRNAs, as well as the relationship of these regulatory pathways with inflammatory processes, so that we can provide a perspective for future studies in the field of diagnosis and possibly treatment of this disorder.

RevDate: 2025-03-25

Simon PYR, R David (2025)

Alzheimer's disease, β-amyloid peptides and ubiquitin-proteasome system: nutritherapeutic insights.

Neuro-degenerative diseases pii:000545170 [Epub ahead of print].

BACKGROUND: The Alzheimer's disease - an age-related neurodegenerative disorder leading to a progressive cognitive impairment - is characterized by an intracerebral accumulation of soluble β-amyloid (Aβ) oligomers, followed by the appearance of abnormally ubiquitinylated neurofibrillary tangles - a process associated with a chronic inflammation. The systematic presence of ubiquitinylated inclusions reflects a decrease in the proteasome activity due to (and contributing to) the presence of Aβ oligomers - a central dysfunction in the etiology of the disease.

SUMMARY: The involvement of the ubiquitin-proteasome system opens new therapeutic perspectives for both prevention and treatment. In particular, the potential for synergistic strategies combining diet-derived proteasome activators, immunoproteasome inhibitors and modulators of β-amyloid peptide aggregation to prevent delay or even reverse the disease progression over time is currently arousing growing interest.

KEY MESSAGES: In that perspective, and in the light of the recent advances in the understanding of the key molecular and cellular mechanisms underlying the Alzheimer's disease pathogenesis, the present review highlights the mechanisms of action and the preventive and therapeutic potential of some diet-derived bioactive compounds and other natural substances of interest. This article is a translated, updated and expanded version of an article originally published in French in Médecine/Sciences, August/September 2023 (https://doi.org/10.1051/medsci/2023094).

RevDate: 2025-03-25
CmpDate: 2025-03-25

Nallapu BT, Petersen KK, Qian T, et al (2025)

A Machine Learning Approach to Predict Cognitive Decline in Alzheimer Disease Clinical Trials.

Neurology, 104(8):e213490.

BACKGROUND AND OBJECTIVES: Among the participants of Alzheimer disease (AD) treatment trials, 40% do not show cognitive decline over 80 weeks of follow-up. Identifying and excluding these individuals can increase power to detect treatment effects. We aimed to develop machine learning-based predictive models to identify persons unlikely to show decline on placebo treatment over 80 weeks.

METHODS: We used the data from the placebo arm of EXPEDITION3 AD clinical trial and a subpopulation from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants in the EXPEDITION3 trial were patients with mild dementia and biomarker evidence of amyloid burden. For this study, participants were identified as those who demonstrated clinically meaningful cognitive decline (CMCD) or cognitively stable (CS) at final visit of the trial (week 80). Machine learning-based classifiers were trained to classify participants into CMCD vs CS groups using combinations of demographics, APOE genotype, neuropsychological tests, and biomarkers (volumetric MRI). The results were developed in 70% of the EXPEDITION3 placebo sample using 5-fold cross-validation. Trained models were then used to classify the participants in an internal validation sample and an external matched sample ADNIAD.

RESULTS: Eight hundred ninety-four of the 1,072 participants in the placebo arm of the EXPEDITION3 trial had necessary follow-up data, who were on average aged 72.7 (±7.7) years and 59% female. 55.8% of those participants showed CMCD (∼2 years younger than those without) at the final visit. In the independent validation sample within the EXPEDITION3 data, all the models showed high sensitivity and modest specificity. Positive predictive values (PPVs) of models were at least 11% higher than base prevalence of CMCD observed at the end of the trial. The subset of matched ADNI participants (ADNIAD, N = 105) were aged 74.5 (±6.4) years and 46% female. The models that were validated in ADNIAD also showed high sensitivity, modest specificity, and PPVs of at least 15% higher than the base prevalence in ADNIAD.

DISCUSSION: Our results indicate that predictive models have the potential to improve the design of AD trials through selective inclusion and exclusion criteria based on expected cognitive decline. Such predictive models need further validation across data from different AD clinical trials.

RevDate: 2025-03-25

Wang J, Liao M, Tong Z, et al (2025)

Treadmill Exercise Modulates the Leptin/LepR/GSK-3β Signalling Pathway to Improve Leptin Sensitivity and Alleviate Neuroinflammation in High-Fat Diet-Fed APP/PS1 Mice.

Molecular neurobiology [Epub ahead of print].

Neuroinflammation plays a critical role in the development of Alzheimer's disease (AD) and is closely associated with obesity. In AD, the fat cell-secreted protein leptin crosses the blood-brain barrier and protects against nerve damage. However, obesity may induce leptin resistance, reduce leptin sensitivity, stimulate excessive glial cell activation, promote inflammatory factor production and exacerbate brain inflammation. Unfortunately, the mechanism of interaction among high-fat diets, obesity, neuroinflammation and neurodegenerative diseases remains unclear. We investigated the changes in neuroinflammation and leptin sensitivity in the brains of wild-type and high-fat-diet-fed APP/PS1 transgenic mice. We explored the effects of treadmill exercise for 12 weeks on the leptin/LepR/GSK-3β signalling pathway and memory. The body weights of the high-fat-diet-fed mice increased, and elevated levels of markers for leptin resistance, including suppressor of signalling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B) and proinflammatory factors such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were observed. After 12 weeks of aerobic exercise, the leptin mRNA and protein levels increased, GSK-3β protein expression decreased and the mean fluorescence intensities of brain microglial (IBA-1) and neuron markers (NeuN) decreased, indicating that exercise may activate the leptin/LepR/GSK-3β signalling pathway, reducing glial cell activation and inflammation. Our study revealed that obesity induces and exacerbates the AD-related neuroinflammatory response. Aerobic exercise activates the leptin/LepR/GSK-3β pathway to relieve neuroinflammation and protect nerve cells, alleviating AD-associated memory loss. These promising outcomes could inform the development of nondrug-based aerobic exercise interventions for the treatment of AD and associated cognitive disorders.

RevDate: 2025-03-25
CmpDate: 2025-03-25

Firoozi A, Shadi M, A Rezagholizadeh (2025)

The role of low-level laser therapy in Alzheimer's disease: a review of the potential benefits of vitamin D enhancement.

Lasers in medical science, 40(1):159.

As the global population ages, neurodegenerative diseases, particularly Alzheimer's disease (AD), have become a major public health concern. AD is the most prevalent neurodegenerative disorder, accounting for 60-80% of cases, and is characterized by progressive cognitive and memory decline due to neuronal loss. Current pharmacological treatments primarily offer symptomatic relief rather than a cure. Recent research has highlighted the role of vitamin D in neuroprotection, owing to its antioxidant, anti-inflammatory, and neuroprotective properties, as well as its ability to maintain blood-brain barrier integrity and regulate amyloid-beta (Aβ) clearance. Another emerging noninvasive therapeutic approach is Low-Level Laser Therapy (LLLT), a form of photobiomodulation (PBM) that has been shown to enhance neuronal function, reduce oxidative stress, inflammation, and Aβ deposition, and potentially increase vitamin D levels. This review examines the interplay between LLLT, vitamin D, and oxidative stress in AD pathophysiology. Findings suggest that LLLT can stimulate mitochondrial function, enhance synaptic plasticity, and improve cognitive performance in preclinical and clinical studies. Furthermore, LLLT has been reported to modulate immune responses, promote neurogenesis, and facilitate vitamin D synthesis by activating cytochrome c oxidase (CCO), which plays a crucial role in mitochondrial energy production. However, while promising, further in vivo and clinical trials are required to optimize treatment protocols and establish standardized guidelines for LLLT application, particularly in enhancing vitamin D levels, in AD patients. CLINICAL TRIAL NUMBER: Not applicable.

RevDate: 2025-03-25

Bilginer-Kartal R, A Arslan-Yildiz (2025)

Magnetic Levitational Assembly of Differentiated SH-SY5Y Cells for Aβ-Induced 3D Alzheimer's Disease Modeling and Curcumin Screening.

Macromolecular bioscience [Epub ahead of print].

Alzheimer's disease is one of the prevalent neurodegenerative diseases and is characterized by amyloid beta aggregate (Aβ) accumulation. This study reports an Aβ 1-42 induced 3D Alzheimer's disease modeling utilizing differentiated SH-SY5Y spheroids, which is carried out by Magnetic levitation approach, and the neuroprotective effect of Curcumin is further investigated on this model. For this purpose, SH-SY5Y spheroids are differentiated using Retinoic acid-Brain-derived neurotrophic factor sequentially during 3D cell culture. Differentiated spheroids maintained high viability and exhibited significant neuronal characteristics, as evidenced by increasing β-III tubulin and NeuN expressions. 3D Alzheimer's disease model formation and neurotoxicity of Aβ 1-42 aggregates are investigated on un-/differentiated spheroids, resulting in 65% and 51% cell viability, respectively. Characterization of the 3D Alzheimer's disease model is done by immunostaining of Choline acetyltransferase to investigate cholinergic neuron activity loss, showing a 2.2 decrease in fluorescence intensity. Further, Curcumin treatment on the 3D Alzheimer's disease model resulted in augmenting cell viability, confirming neuroprotective effect of Curcumin on Aβ 1-42 induced Alzheimer's disease model. This study highlighted the magnetic levitation-based fabrication of Aβ 1-42-induced 3D Alzheimer's disease model successfully, offering a promising experimental platform for other neurodegenerative disease research and potential clinical applications.

RevDate: 2025-03-25

Yang Q, Qiu Y, Ni J, et al (2025)

Deciphering T Cell Dynamics in Alzheimer's Disease Pathogenesis: Insights and Implications.

Current neuropharmacology pii:CN-EPUB-147315 [Epub ahead of print].

Neuroinflammation has emerged as a crucial factor in the pathogenesis of Alzheimer's disease (AD), paving the way for promising therapeutic interventions. Increasing evidence highlights the interplay between the peripheral immune system and the central nervous system (CNS) in driving neuroinflammation, with T lymphocytes playing a vital role in both regulatory and effector functions. Aberrant activation of T cells during the early stages of neuroinflammation perpetuates inflammatory responses by interacting with CNS glial cells and releasing pro-inflammatory mediators, such as IFN-γ, TNF-α, and IL-17. Studies have documented significant T cell activation and infiltration into the brain parenchyma in AD, contributing to disease progression. However, the specific mechanisms by which T cells mediate AD pathogenesis remain unclear. This comprehensive review synthesizes the current understanding of T cell involvement in AD pathology, emphasizing their aberrant activation, interactions with microglia, tau protein pathology, and the influence of gut microbiota. Finally, we propose potential treatment modalities for AD, highlighting the promise of T cellbased therapies currently under investigation in clinical trials. Understanding the critical role of T cells in intercellular communication and disease progression may enhance our comprehension of the pathophysiology of AD.

RevDate: 2025-03-25
CmpDate: 2025-03-25

Lolak N, Akocak S, Topal M, et al (2025)

Sulfonamide-Bearing Pyrazolone Derivatives as Multitarget Therapeutic Agents: Design, Synthesis, Characterization, Biological Evaluation, In Silico ADME/T Profiling and Molecular Docking Study.

Pharmacology research & perspectives, 13(2):e70088.

The research and design of new inhibitors for the treatment of diseases such as Alzheimer's disease and glaucoma through inhibition of cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and carbonic anhydrase enzymes are among the important targets. Here, a series of novel sulfonamide-bearing pyrazolone derivatives (1a-f and 2a-f) were successfully synthesized and characterized by using spectroscopic and analytical methods. The inhibitory activities of these newly synthesized compounds were evaluated both in vitro and in silico for their effect on carbonic anhydrases (hCA I and hCA II isoenzymes) and ChEs. The in vitro studies showed that these novel compounds demonstrated potential inhibitory activity, with KI values covering the following ranges: 18.03 ± 2.86-75.54 ± 4.91 nM for hCA I, 24.84 ± 1.57-85.42 ± 6.60 nM for hCA II, 7.45 ± 0.98-16.04 ± 1.60 nM for AChE, and 34.78 ± 5.88-135.70 ± 17.39 nM for BChE. Additionally, many of these compounds showed promising inhibitory activity, and some showed higher potency than reference compounds. While the in silico studies have also identified the potential binding positions of these compounds, using the crystal structures of hCA I, II, AChE and BChE receptors. The varying affinities demonstrated by these designed compounds for ChEs and hCA isoenzymes show that these compounds could hold promise as potential alternative agents for selectively inhibiting ChEs and hCAs in the treatment of diseases such as Alzheimer's disease and glaucoma.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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