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30 Mar 2023 at 01:34
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Bibliography on: Alzheimer Disease — Current Literature


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RJR: Recommended Bibliography 30 Mar 2023 at 01:34 Created: 

Alzheimer Disease — Current Literature

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. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: 2021:2023[dp] AND ( alzheimer*[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2023-03-29

Fukunaga K (2023)

[Development of demetia therapeutics regurating synaptic plasticity].

Nihon yakurigaku zasshi. Folia pharmacologica Japonica [Epub ahead of print].

Alzheimer's disease (AD) is the most common dementia in the world characterized by the neuropathological hallmarks consisting of an accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT). There is no fundamental therapeutic treatment. We have developed a novel AD therapeutic candidate SAK3 which improves neuronal plasticity in the brain. SAK3 enhanced the acetylcholine release via T-type calcium channels. T-type calcium channels is highly expressed in neuro-progenitor cells in the hippocampal dentate gyrus. SAK3 enhanced the proliferation and differentiation of the neuro-progenitor cells, thereby improving depressive behaviors. The Cav3.1 null mice impaired the proliferation and differentiation of the neuro-progenitor cells. In addition, SAK3 activated CaMKII involving neuronal plasticity, thereby improving spine regeneration and proteasome activities impaired in AD related App[NL-F/NL-F] knock-in mice. The improvement of the decreased proteasome activity through enhancement CaMKII/Rpt6 signaling by SAK3 treatment contributed to the amelioration of synaptic abnormalities and cognitive decline. The increased proteasome activity also accounted for inhibition of Aβ deposition. Taken together, the proteasome activation via enhancement of CaMKII/Rpt6 signaling is a new strategy for AD treatment, which rescues the AD pathology including cognitive impairments and Aβ deposition. SAK3 may be a new hopeful drug candidate rescuing dementia patients.

RevDate: 2023-03-29

Sekimitsu S, Shweikh Y, Shareef S, et al (2023)

Association of retinal optical coherence tomography metrics and polygenic risk scores with cognitive function and future cognitive decline.

The British journal of ophthalmology pii:bjo-2022-322762 [Epub ahead of print].

PURPOSE: To evaluate the potential of retinal optical coherence tomography (OCT) measurements and polygenic risk scores (PRS) to identify people at risk of cognitive impairment.

METHODS: Using OCT images from 50 342 UK Biobank participants, we examined associations between retinal layer thickness and genetic risk for neurodegenerative disease and combined these metrics with PRS to predict baseline cognitive function and future cognitive deterioration. Multivariate Cox proportional hazard models were used to predict cognitive performance. P values for retinal thickness analyses are false-discovery-rate-adjusted.

RESULTS: Higher Alzheimer's disease PRS was associated with a thicker inner nuclear layer (INL), chorio-scleral interface (CSI) and inner plexiform layer (IPL) (all p<0.05). Higher Parkinson's disease PRS was associated with thinner outer plexiform layer (p<0.001). Worse baseline cognitive performance was associated with thinner retinal nerve fibre layer (RNFL) (aOR=1.038, 95% CI (1.029 to 1.047), p<0.001) and photoreceptor (PR) segment (aOR=1.035, 95% CI (1.019 to 1.051), p<0.001), ganglion cell complex (aOR=1.007, 95% CI (1.002 to 1.013), p=0.004) and thicker ganglion cell layer (aOR=0.981, 95% CI (0.967 to 0.995), p=0.009), IPL (aOR=0.976, 95% CI (0.961 to 0.992), p=0.003), INL (aOR=0.923, 95% CI (0.905 to 0.941), p<0.001) and CSI (aOR=0.998, 95% CI (0.997 to 0.999), p<0.001). Worse future cognitive performance was associated with thicker IPL (aOR=0.945, 95% CI (0.915 to 0.999), p=0.045) and CSI (aOR=0.996, 95% CI (0.993 to 0.999) 95% CI, p=0.014). Prediction of cognitive decline was significantly improved with the addition of PRS and retinal measurements.

CONCLUSIONS AND RELEVANCE: Retinal OCT measurements are significantly associated with genetic risk of neurodegenerative disease and may serve as biomarkers predictive of future cognitive impairment.

RevDate: 2023-03-29

Allam I, Gresham M, Phillipson L, et al (2023)

Beliefs around help-Seeking and Support for Dementia in the Australian Arabic Speaking Community.

Dementia (London, England) [Epub ahead of print].

BACKGROUND: The number of people with dementia in multicultural Australia is rapidly increasing. Despite its culturally diverse population, there is limited research about how people from ethnic minority groups understand and approach help-seeking and support for dementia. The aim of this study is to understand the perceptions of dementia symptoms, help-seeking and support in the Australian Arabic-speaking community.

METHODS: This study used a cross-sectional qualitative research design. Individual, semi-structured interviews using projective stimulus techniques were used. Participants were three Arabic-speaking people aged over 70 who were experiencing cognitive changes or dementia symptoms, six carers, and five health or social care practitioners experienced in working with Arab-Australians. Phone or video chat interviews were conducted in either Arabic or English. Interviews were audiotaped, translated when needed, transcribed verbatim and inductive thematic analysis was undertaken.

FINDINGS: Seven themes were identified. Participants described dementia as relating to symptoms of confusion and memory loss. Carers and older people believe that when older people are experiencing these cognitive symptoms, they must be cared for primarily by ensuring their happiness and comfort. Barriers to help-seeking and support included a lack of help-seeking due to cultural norms of family orientated care, families are unsure of where to seek help and fear of community judgement. Two ways to facilitate help-seeking and support were to build trust through culturally appropriate support and to educate the community.

CONCLUSION: Family, trust and community were identified as central pillars of the Australian-Arabic-speaking community. There is a need to increase dementia literacy in this community particularly around help-seeking and decreasing stigma. Education should be promoted by trusted community members and religious leaders. As the first point of professional contact, general practitioners need to be upskilled to support Arabic-speaking Australians around dementia.

RevDate: 2023-03-29

Ali SM, Nabi F, Furkan M, et al (2023)

Tuning the aggregation behavior of human insulin in the presence of luteolin: An in vitro and in silico approach.

International journal of biological macromolecules pii:S0141-8130(23)01113-3 [Epub ahead of print].

Protein misfolding and related formation of amyloid fibrils are associated with several conformational diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), prion diseases, and Diabetes mellitus, Type 2 (DM-II). Several molecules including antibiotics, polyphenols, flavonoids, anthraquinones, and other small molecules are implicated to modulate amyloid assembly. The stabilization of the native forms of the polypeptides and prevention of their misfolding and aggregation are of clinical and biotechnological importance. Among the natural flavonoids, luteolin is of great importance because of its therapeutic role against neuroinflammation. Herein, we have explored the inhibitory effect of luteolin (LUT) on aggregation of a model protein, human insulin (HI). To understand the molecular mechanism of the inhibition of aggregation of HI by LUT, we employed molecular simulation, UV-Vis, fluorescence, and circular dichroism (CD) spectroscopies along with the dynamic light scattering (DLS). The analysis of the tuning of the HI aggregation process by luteolin revealed that interaction of HI with LUT resulted in the decrease in binding of the various fluorescent dyes, such as thioflavin T (ThT) and 8-anilinonaphthalene-1-sulfonic acid (ANS) to this protein. Retention of the native-like CD spectra and resistance to the aggregation in the presence of LUT has confirmed the aggregation inhibitory potential of LUT. The maximum inhibitory effect was found at the protein-to-drug ratio of 1:12, and no significant change was observed beyond this concentration.

RevDate: 2023-03-29

Guzzardi MA, Rosa F, P Iozzo (2023)

Trust the gut: outcomes of gut microbiota transplant in metabolic and cognitive disorders.

Neuroscience and biobehavioral reviews pii:S0149-7634(23)00112-4 [Epub ahead of print].

Type 2 diabetes mellitus (T2DM) is a main public health concern, with increasing prevalence and growingly premature onset in children, in spite of emerging and successful therapeutic options. T2DM promotes brain aging, and younger age at onset is associated with a higher risk of subsequent dementia. Preventive strategies should address predisposing conditions, like obesity and metabolic syndrome, and be started from very early and even prenatal life. Gut microbiota is an emerging target in obesity, diabetes and neurocognitive diseases, which could be safely modulated since pregnancy and infancy. Many correlative studies have supported its involvement in disease pathophysiology. Faecal material transplantation (FMT) studies have been conducted in clinical and preclinical settings to deliver cause-effect proof and mechanistic insights. This review provides a comprehensive overview of studies in which FMT was used to cure or cause obesity, metabolic syndrome, T2DM, cognitive decline and Alzheimer's disease, including the evidence available in early life. Findings were analysed to dissect consolidated from controversial results, highlighting gaps and possible future directions.

RevDate: 2023-03-29

Pedersen TJ, Keil SA, Han W, et al (2023)

The effect of aquaporin-4 mis-localization on Aβ deposition in mice.

Neurobiology of disease pii:S0969-9961(23)00114-6 [Epub ahead of print].

The reduced clearance of amyloid-β (Aβ) is thought to contribute to the development of the pathology associated with Alzheimer's disease (AD), which is characterized by the deposition of Aβ plaques. Previous studies have shown that Aβ is cleared via the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is dependent upon the water channel aquaporin-4 (AQP4), localized at astrocytic endfeet. While prior studies have shown that both the loss and mislocalization of AQP4 slow Aβ clearance and promote Aβ plaque formation, the relative impact of the loss or mislocalization of AQP4 on Aβ deposition has never been directly compared. In this study, we evaluated how the deposition of Aβ plaques within the 5XFAD mouse line is impacted by either Aqp4 gene deletion or the loss of AQP4 localization in the α-syntrophin (Snta1) knockout mouse. We observed that both the absence (Aqp4 KO) and mislocalization (Snta1 KO) of AQP4 significantly increases the parenchymal Aβ plaque and microvascular Aβ deposition across the brain, when compared with 5XFAD littermate controls. Further, the mislocalization of AQP4 had a more pronounced impact on Aβ plaque deposition than did global Aqp4 gene deletion, perhaps pointing to a key role that mislocalization of perivascular AQP4 plays in AD pathogenesis .

RevDate: 2023-03-29

Ferrer (1st) (2023)

The unique neuropathological vulnerability of the human brain to aging.

Ageing research reviews pii:S1568-1637(23)00075-2 [Epub ahead of print].

Alzheimer's disease (AD)-related neurofibrillary tangles (NFT), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), limbic predominant TDP-43 proteinopathy (LATE), and amygdala-predominant Lewy body disease (LBD) are proteinopathies that, together with hippocampal sclerosis, progressively appear in the elderly affecting from 50% to 99% of individuals aged 80 years, depending on the disease. These disorders usually converge on the same subject and associate with additive cognitive impairment. Abnormal Tau, TDP-43, and α-synuclein pathologies progress following a pattern consistent with an active cell-to-cell transmission and abnormal protein processing in the host cell. However, cell vulnerability and transmission pathways are specific for each disorder, albeit abnormal proteins may co-localize in particular neurons. All these alterations are unique or highly prevalent in humans. They all affect, at first, the archicortex and paleocortex to extend at later stages to the neocortex and other regions of the telencephalon. These observations show that the phylogenetically oldest areas of the human cerebral cortex and amygdala are not designed to cope with the lifespan of actual humans. New strategies aimed at reducing the functional overload of the human telencephalon, including optimization of dream repair mechanisms and implementation of artificial circuit devices to surrogate specific brain functions, appear promising.

RevDate: 2023-03-29

Tiwari A, Pradhan S, Sannigrahi A, et al (2023)

"Interplay of lipid-head group and packing defects in driving Amyloid-beta mediated myelin-like model membrane deformation".

The Journal of biological chemistry pii:S0021-9258(23)00295-8 [Epub ahead of print].

Accumulating evidence suggests that amyloid plaque associated myelin lipid loss as a result of elevated amyloid burden might also contribute to Alzheimer's disease. The amyloid fibrils though closely associated with lipids under physiological conditions, however, the progression of membrane remodeling events leading to lipid-fibril assembly remains unknown. Here we first reconstitute the interaction of Aβ-40 with myelin-like model membrane and show that the binding of Aβ-40 induces extensive tubulation. To look into the mechanism of membrane tubulation we chose a set of membrane conditions varying in lipid packing density and net charge that allows us to dissect the contribution of lipid specificity of Aβ-40 binding, aggregation kinetics, and subsequent changes in membrane parameters such as fluidity, diffusion, and compressibility modulus. We show that the binding of Aβ-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin-like model membrane during the early phase of amyloid aggregation. Furthermore, elongation of Aβ-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the model membrane followed by extensive lipid membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aβ-40 - myelin-like model membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril-mediated load generation results in the consequent association of lipids with growing amyloid fibrils.

RevDate: 2023-03-29

Du K, Dou Y, Chen K, et al (2023)

Activation of TRPV4 induces intraneuronal tau hyperphosphorylation via cholesterol accumulation.

Experimental neurology pii:S0014-4886(23)00076-6 [Epub ahead of print].

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel, whose aberrant function in neurons has been reported to participate in the progression of brain disorders, including Alzheimer's disease (AD). However, the influence of TRPV4 activation on tau hyperphosphorylation in AD has not yet been elucidated. Since disturbed brain cholesterol homeostasis is considered to be related to excessive tau phosphorylation, this study aimed to explore whether dysregulation of TRPV4 affects tau phosphorylation and whether it involves cholesterol unbalance. Our data indicated that TRPV4 activation increased tau phosphorylation in the cortex and hippocampus of P301S tauopathy mouse model and aggravated its cognitive decline. In addition, we detected that TRPV4 activation upregulated cholesterol levels in primary neurons, and the elevation of cholesterol promoted hyperphosphorylation of tau. TRPV4 knockdown improved tau hyperphosphorylation by reducing intracellular cholesterol accumulation. Our results suggest that activation of TRPV4 may take part in the pathological mechanism of AD by promoting intraneuronal tau hyperphosphorylation in a cholesterol-dependent manner.

RevDate: 2023-03-29

Fei Y, Wang R, Lu J, et al (2023)

Probiotic intervention benefits multiple neural behaviors in older adults with mild cognitive impairment.

Geriatric nursing (New York, N.Y.), 51:167-175 pii:S0197-4572(23)00060-5 [Epub ahead of print].

Probiotic supplements were shown to improve cognitive function in Alzheimer's disease (AD) patients. However, it is still unclear whether this applies to older individuals with mild cognitive impairment (MCI). We aimed to explore the effects of probiotic supplementation on multiple neural behaviors in older adults with MCI. Forty-two MCI patients (age > 60 years) were randomly divided into two groups and consumed either probiotics (n=21) or placebo (n=21) for 12 weeks. Various scale scores, gut microbiota measures and serological indicators were recorded pre- and posttreatment. After 12 weeks of intervention, cognitive function and sleep quality were improved in the probiotic group compared with those in the control group, and the underlying mechanisms were associated with changes in the intestinal microbiota. In conclusion, our study demonstrated that probiotic treatment enhanced cognitive function and sleep quality in older MCI patients, thus providing important insights into the clinical prevention and treatment of MCI.

RevDate: 2023-03-29

Kovaleva MA, Kleinpell R, Dietrich MS, et al (2023)

Caregivers' experience with Tele-Savvy Caregiver Program post-hospitalization.

Geriatric nursing (New York, N.Y.), 51:156-166 pii:S0197-4572(23)00055-1 [Epub ahead of print].

Despite the frequent hospitalizations and readmissions of persons living with dementia (PLWD), no telehealth transitional care interventions focus on PLWDs' unpaid caregivers. Tele-Savvy Caregiver Program is a 43-day evidence-based online psychoeducational intervention for PLWDs' caregivers. The aim of this formative evaluation was to explore caregivers' acceptability of and experience with their participation in Tele-Savvy after their PLWDs' hospital discharge. Additionally, we gathered caregivers' feedback on the recommended features of a transitional care intervention, suitable for caregivers' schedule and needs post-discharge. Fifteen caregivers completed the interviews. Data were analyzed via conventional content analysis. Four categories were identified: (1) Tele-Savvy improved participants' understanding of dementia and caregiving; (2) hospitalization started a "new level of normal"; (3) PLWDs' health concerns; and (4) transitional care intervention development. Participation in Tele-Savvy was acceptable for most caregivers. Participants' feedback provides content and structural guidance for the development of a new transitional care intervention for PLWDs' caregivers.

RevDate: 2023-03-29

Yang R, Liu J, L Zhang (2023)

ECAmyloid: An amyloid predictor based on ensemble learning and comprehensive sequence-derived features.

Computational biology and chemistry, 104:107853 pii:S1476-9271(23)00044-0 [Epub ahead of print].

Amyloid fibrils formed by the mis-aggregation of amyloid proteins can lead to neuronal degenerations in the Alzheimer's disease. Predicting amyloid proteins not only contributes to understanding physicochemical properties and formation mechanism of amyloid proteins, but also has significant implications in the amyloid disease treatment and the development of a new purpose for amyloid materials. In this study, an ensemble learning model with sequence-derived features, ECAmyloid, is proposed to identify amyloids. The sequence-derived features including Pseudo Position Specificity Score Matrix (Pse-PSSM), Split Amino Acid Composition (SAAC), Solvent Accessibility (SA), and Secondary Structure Information (SSI) are employed to incorporate sequence composition, evolutionary and structural information. The individual learners of the ensemble learning model are selected by an increment classifier selection strategy. The final prediction results are determined by voting of prediction results of multiple individual learners. In view of the imbalanced benchmark dataset, the Synthetic Minority Over-sampling Technique (SMOTE) is adopted to generate positive samples. To eliminate irrelevant features and redundant features, correlation-based feature subset (CFS) selection combined with a heuristic search strategy is performed to obtain the optimal feature subset. Experimental results indicate that the ensemble classifier achieves an accuracy of 98.29%, a sensitivity of 0.992, a specificity of 0.974 on the training dataset using the 10-fold cross validation, far higher than the results obtained by its individual learners. Compared with the original feature set, the accuracy, sensitivity, specificity, MCC, F1-score, G-Mean of the ensemble method trained by the optimal feature subset are improved by 1.05%, 0.012, 0.01, 0.021, 0.011 and 0.011, respectively. Moreover, the comparison results with existing methods on two same independent test datasets demonstrate that the proposed method is an effective and promising predictor for large-scale determination of amyloid proteins. The data and code used to develop ECAmyloid has been shared to Github, and can be freely downloaded at https://github.com/KOALA-L/ECAmyloid.git.

RevDate: 2023-03-29

Lee TS, Park EJ, Choi M, et al (2023)

Novel LC-MS/MS analysis of the GLP-1 analog semaglutide with its application to pharmacokinetics and brain distribution studies in rats.

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1221:123688 pii:S1570-0232(23)00098-3 [Epub ahead of print].

Semaglutide, one of the most potent glucagon-like peptide (GLP)-1 analogs, has widely been used to treat type II diabetes mellitus and obesity. Recent studies have shown that semaglutide also works on the brain, suggesting its potential utility for various diseases, including Parkinson's disease and Alzheimer's disease. This study aimed to develop a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of semaglutide in both plasma and brain to characterize the pharmacokinetics and brain distribution in rats. Semaglutide was extracted by simple protein precipitation with methanol from plasma and by solid phase extraction from brain tissue. Liraglutide was used as an internal standard. Gradient elution profiles with mobile phases comprising 0.1 % formic acid in water and acetonitrile were used for chromatographic separation. The lower limit of quantification (LLOQ) of the LC-MS/MS assay was 0.5 ng/mL for both rat plasma and brain. Intra- and inter-day accuracy ranged 89.20-109.50 % in the plasma and 92.00-105.00 % in the brain. Precision was within 8.92 % in the plasma and 7.94 % in the brain. Sprague-Dawley rats were given semaglutide by intravenous (IV, 0.02 mg/kg) and subcutaneous (SC, 0.1 and 0.2 mg/kg) injection. Plasma concentrations of semaglutide showed a multi-exponential decline with an average half-life of 7.22-9.26 hr in rats. The subcutaneous bioavailability of semaglutide was 76.65-82.85 %. The brain tissue to plasma partition coefficient (Kp) value of semaglutide was estimated as <0.01. Among the different regions of the brain, semaglutide concentrations were significantly higher in the hypothalamus. The analytical method and pharmacokinetic information may be helpful toward a better understanding of the effect of semaglutide in the brain and further development of GLP-1 analogs for various brain diseases.

RevDate: 2023-03-29

Kenyaga JM, Oteino SA, Sun Y, et al (2023)

In-cell [31]P solid-state NMR measurements of the lipid dynamics and influence of exogeneous β-amyloid peptides on live neuroblastoma neuro-2a cells.

Biophysical chemistry, 297:107008 pii:S0301-4622(23)00059-5 [Epub ahead of print].

Non-specific disruption of cellular membranes induced by aggregation of exogeneous β-amyloid (Aβ) peptides is considered a viable pathological mechanism in Alzheimer's disease (AD). The solid-state nuclear magnetic resonance (ssNMR) spectroscopy has been widely applied in model liposomes to provide important insights on the molecular interactions between membranes and Aβ aggregates. Yet, the feasibility of in-cell ssNMR spectroscopy to probe Aβ-membrane interactions in native cellular environments has rarely been tested. Here we report the application of in-cell[31]P ssNMR spectroscopy on live mouse neuroblastoma Neuro-2a (N2a) cells under moderate magic angle spinning (MAS) conditions. Both cell viability and cytoplasmic membrane integrity are retained for up to six hours under 5 kHz MAS frequency at 277 K, which allow applications of direct-polarization [31]P spectroscopy and [31]P spin-spin (T2) relaxation measurements. The [31]P T2 relaxation time constant of N2a cells is significantly increased compared with the model liposome prepared with comparable major phospholipid compositions. With the addition of 5 μM 40-residue Aβ (Aβ1-40) peptides, the [31]P T2 relaxation is instantly accelerated. This work demonstrates the feasibility of using in-cell[31]P ssNMR to investigate the Aβ-membrane interactions in the biologically relevant cellular system.

RevDate: 2023-03-29

Chan K, Fischer C, Maralani PJ, et al (2023)

Alzheimer's and vascular disease classification using regional texture biomarkers in FLAIR MRI.

NeuroImage. Clinical, 38:103385 pii:S2213-1582(23)00074-8 [Epub ahead of print].

Interactions between subcortical vascular disease and dementia due to Alzheimer's disease (AD) are unclear, and clinical overlap between the diseases makes diagnosis challenging. Existing studies have shown regional microstructural changes specific to each disease, and that textures in fluid-attenuated inversion recovery (FLAIR) MRI images may characterize abnormalities in tissue microstructure. This work aims to investigate regional FLAIR biomarkers that can differentiate dementia cohorts with and without subcortical vascular disease. FLAIR and diffusion MRI (dMRI) volumes were obtained in 65 mild cognitive impairment (MCI), 21 AD, 44 subcortical vascular MCI (scVMCI), 22 Mixed etiology, and 48 healthy elderly patients. FLAIR texture and intensity biomarkers were extracted from the normal appearing brain matter (NABM), WML penumbra, blood supply territory (BST), and white matter tract regions of each patient. All FLAIR biomarkers were correlated to dMRI metrics in each region and global WML load, and biomarker means between groups were compared using ANOVA. Binary classifications were performed using Random Forest classifiers to investigate the predictive nature of the regional biomarkers, and SHAP feature analysis was performed to further investigate optimal regions of interest for differentiating disease groups. The regional FLAIR biomarkers were strongly correlated to MD, while all biomarker regions but white matter tracts were strongly correlated to WML burden. Classification between Mixed disease and healthy, AD, and scVMCI patients yielded accuracies of 97%, 81%, and 72% respectively using WM tract biomarkers. Classification between scVMCI and healthy, MCI, and AD patients yielded accuracies of 89%, 84%, and 79% respectively using penumbra biomarkers. Only the classification between AD and healthy patients had optimal results using NABM biomarkers. This work presents novel regional FLAIR biomarkers that may quantify white matter degeneration related to subcortical vascular disease, and which indicate that investigating degeneration in specific regions may be more important than assessing global WML burden in vascular disease groups.

RevDate: 2023-03-29

Panes-Fernandez J, Godoy PA, Gavilan J, et al (2023)

TG2 promotes amyloid beta aggregates: Impact on ER-mitochondria crosstalk, calcium homeostasis and synaptic function in Alzheimer's disease.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 162:114596 pii:S0753-3322(23)00384-0 [Epub ahead of print].

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly affects the elderly. AD's main features have been related to cellular and molecular events, including the aberrant aggregation of the amyloid beta peptide (Aβ), Ca[2+] dyshomeostasis, and increased mitochondria-associated membranes (MAMs). Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose primary role is the Ca[2+]-dependent proteins transamidation, including the Aβ peptide. TG2 activity has been closely related to cellular damage and death. We detected increased TG2 levels in neuronal cells treated with Aβ oligomers (AβOs) and hippocampal slices from J20 mice using cellular and molecular approaches. In this work, we characterized the capacity of TG2 to interact and promote Aβ toxic aggregates (AβTG2). AβTG2 induced an acute increase in intracellular Ca[2+], miniature currents, and hiperexcitability, consistent with an increased mitochondrial Ca[2+] overload, IP3R-VDAC tethering, and mitochondria-endoplasmic reticulum contacts (MERCs). AβTG2 also decreased neuronal viability and excitatory postsynaptic currents, reinforcing the idea of synaptic failure associated with MAMs dysregulation mediated by TG2. Z-DON treatment, TG2 inhibitor, reduced calcium overload, mitochondrial membrane potential loss, and synaptic failure, indicating an involvement of TG2 in a toxic cycle which increases Aβ aggregation, Ca[2+] overload, and MAMs upregulation. These data provide novel information regarding the role TG2 plays in synaptic function and contribute additional evidence to support the further development of TG2 inhibitors as a disease-modifying strategy for AD.

RevDate: 2023-03-29

Lv J, Xing L, Zhong X, et al (2023)

Role of N6-methyladenosine modification in central nervous system diseases and related therapeutic agents.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 162:114583 pii:S0753-3322(23)00371-2 [Epub ahead of print].

N6-methyladenosine (m6A) is a ubiquitous mRNA modification in eukaryotes. m6A occurs through the action of methyltransferases, demethylases, and methylation-binding proteins. m6A methylation of RNA is associated with various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), depression, cerebral apoplexy, brain injury, epilepsy, cerebral arteriovenous malformations, and glioma. Furthermore, recent studies report that m6A-related drugs have attracted considerable concerns in the therapeutic areas of neurological disorders. Here, we mainly summarized the role of m6A modification in neurological diseases and the therapeutic potential of m6A-related drugs. The aim of this review is expected to be useful to systematically assess m6A as a new potential biomarker and develop innovative modulators of m6A for the amelioration and treatment of neurological disorders.

RevDate: 2023-03-29

Keszycki R, Rodriguez G, Dunn JT, et al (2023)

Characterization of apathy-like behaviors in the 5xFAD mouse model of Alzheimer's disease.

Neurobiology of aging, 126:113-122 pii:S0197-4580(23)00045-3 [Epub ahead of print].

Most patients with Alzheimer's disease (AD) develop neuropsychiatric symptoms (NPS) alongside cognitive decline, and apathy is one of the most common symptoms. Few preclinical studies have investigated the biological substrates underlying NPS in AD. In this study, we used a cross-sectional design to characterize apathy-like behaviors and assess memory in 5xFAD and wildtype control mice at 6, 12, and 16 months of age. Nest building, burrowing, and marble burying were used to test representative behaviors of apathy, and a composite score of apathy-like behavior was generated from these assays. Soluble Aβ42 and plaques were quantified in the prefrontal cortex and hippocampus of the 5xFAD mice with the highest and lowest composite scores using ELISA and histology. Results suggest that 5xFAD mice develop significant apathy-like behaviors starting at 6 months of age that worsen with aging and are positively correlated with soluble Aβ42 and plaques in the prefrontal cortex and hippocampus. Our findings highlight the utility of studying NPS in mouse models of AD to uncover important relationships with underlying neuropathology.

RevDate: 2023-03-29

Mahady LJ, Perez SE, Malek-Ahmadi M, et al (2023)

Oligomeric, phosphorylated, and truncated tau and spliceosome pathology within the entorhinal-hippocampal connectome across stages of Alzheimer's disease.

The Journal of comparative neurology [Epub ahead of print].

Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the density of posttranslational oligomeric (TOC1 and TNT1), phosphorylated (AT8), and late truncated (TauC3) tau epitopes within the MTL subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Although a significant increase in TOC1, TNT1, and AT8 neuron density occurred in the EC in MCI and AD, subicular, DG granule cell, and CA1 and CA3 densities were only significantly higher in AD. TauC3 counts were not different between connectome regions and clinical groups. SRSF2 intensity in AT8-positive cells decreased significantly in all regions independent of the clinical groups examined. CA1 and subicular AT8, TauC3, and oligomeric densities correlated across clinical groups. EC AT8 counts correlated with CA subfields and subicular and DG values across clinical groups. Oligomeric and AT8 CA1, EC, and subicular density correlated with Braak stage. Decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated tau suggests a dual-hit process in NFT formation within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal-hippocampal connectome.

RevDate: 2023-03-29

Zhou J, Wade SD, Graykowski D, et al (2023)

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration.

Science translational medicine, 15(689):eadf0141.

Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD.

RevDate: 2023-03-29

Boster KAS, Cai S, Ladrón-de-Guevara A, et al (2023)

Artificial intelligence velocimetry reveals in vivo flow rates, pressure gradients, and shear stresses in murine perivascular flows.

Proceedings of the National Academy of Sciences of the United States of America, 120(14):e2217744120.

Quantifying the flow of cerebrospinal fluid (CSF) is crucial for understanding brain waste clearance and nutrient delivery, as well as edema in pathological conditions such as stroke. However, existing in vivo techniques are limited to sparse velocity measurements in pial perivascular spaces (PVSs) or low-resolution measurements from brain-wide imaging. Additionally, volume flow rate, pressure, and shear stress variation in PVSs are essentially impossible to measure in vivo. Here, we show that artificial intelligence velocimetry (AIV) can integrate sparse velocity measurements with physics-informed neural networks to quantify CSF flow in PVSs. With AIV, we infer three-dimensional (3D), high-resolution velocity, pressure, and shear stress. Validation comes from training with 70% of PTV measurements and demonstrating close agreement with the remaining 30%. A sensitivity analysis on the AIV inputs shows that the uncertainty in AIV inferred quantities due to uncertainties in the PVS boundary locations inherent to in vivo imaging is less than 30%, and the uncertainty from the neural net initialization is less than 1%. In PVSs of N = 4 wild-type mice we find mean flow speed 16.33 ± 11.09 µm/s, volume flow rate 2.22 ± 1.983 × 10[3] µm[3]/s, axial pressure gradient (- 2.75 ± 2.01)×10[-4] Pa/µm (-2.07 ± 1.51 mmHg/m), and wall shear stress (3.00 ± 1.45)×10[-3] Pa (all mean ± SE). Pressure gradients, flow rates, and resistances agree with prior predictions. AIV infers in vivo PVS flows in remarkable detail, which will improve fluid dynamic models and potentially clarify how CSF flow changes with aging, Alzheimer's disease, and small vessel disease.

RevDate: 2023-03-29

Fredi BM, De Labio RW, Rasmussen LT, et al (2023)

CDK10, CDK11, FOXO1, and FOXO3 Gene Expression in Alzheimer's Disease Encephalic Samples.

Cellular and molecular neurobiology [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neuroinflammatory and neurodegenerative disorder that affects different regions of the brain. Its pathophysiology includes the accumulation of β-amyloid protein, formation of neurofibrillary tangles, and inflammatory processes. Genetic factors are involved in the onset of AD, but they are not fully elucidated. Identification of gene expression in encephalic tissues of patients with AD may help elucidate its development. Our objectives were to characterize and compare the gene expression of CDK10, CDK11, FOXO1, and FOXO3 in encephalic tissue samples from AD patients and elderly controls, from the auditory cortex and cerebellum. RT-qPCR was used on samples from 82 individuals (45 with AD and 37 controls). We observed a statistically significant increase in CDK10 (p = 0.029*) and CDK11 (p = 0.048*) gene expression in the AD group compared to the control, which was most evident in the cerebellum. Furthermore, the Spearman test demonstrated the presence of a positive correlation of gene expression both in the auditory cortex in the AD group (r = 0.046/p = 0.004) and control group (r = 0.454/p = 0.005); and in the cerebellum in the AD group (r = 0.654 /p < 0.001). There was no statistically significant difference and correlation in the gene expression of FOXO1 and FOXO3 in the AD group and the control. In conclusion, CDK10 and CDK11 have high expression in AD patients compared to control, and they present a positive correlation of gene expression in the analyzed groups and tissues, which suggests that they play an important role in the pathogenesis of AD.

RevDate: 2023-03-29

Pan M, Li X, Xu G, et al (2023)

Tripartite Motif Protein Family in Central Nervous System Diseases.

Cellular and molecular neurobiology [Epub ahead of print].

Tripartite motif (TRIM) protein superfamily is a group of E3 ubiquitin ligases characterized by the conserved RING domain, the B-box domain, and the coiled-coil domain (RBCC). It is widely involved in various physiological and pathological processes, such as intracellular signal transduction, cell cycle regulation, oncogenesis, and innate immune response. Central nervous system (CNS) diseases are composed of encephalopathy and spinal cord diseases, which have a high disability and mortality rate. Patients are often unable to take care of themselves and their life quality can be seriously declined. Initially, the function research of TRIM proteins mainly focused on cancer. However, in recent years, accumulating attention is paid to the roles they play in CNS diseases. In this review, we integrate the reported roles of TRIM proteins in the pathological process of CNS diseases and related signaling pathways, hoping to provide theoretical bases for further research in treating CNS diseases targeting TRIM proteins. TRIM proteins participated in CNS diseases. TRIM protein family is characterized by a highly conserved RBCC domain, referring to the RING domain, the B-box domain, and the coiled-coil domain. Recent research has discovered the relations between TRIM proteins and various CNS diseases, especially Alzheimer's disease, Parkinson's disease, and ischemic stroke.

RevDate: 2023-03-29

Jing R, Chen P, Wei Y, et al (2023)

Altered large-scale dynamic connectivity patterns in Alzheimer's disease and mild cognitive impairment patients: A machine learning study.

Human brain mapping [Epub ahead of print].

Alzheimer's disease (AD) is a common neurodegeneration disease associated with substantial disruptions in the brain network. However, most studies investigated static resting-state functional connections, while the alteration of dynamic functional connectivity in AD remains largely unknown. This study used group independent component analysis and the sliding-window method to estimate the subject-specific dynamic connectivity states in 1704 individuals from three data sets. Informative inherent states were identified by the multivariate pattern classification method, and classifiers were built to distinguish ADs from normal controls (NCs) and to classify mild cognitive impairment (MCI) patients with informative inherent states similar to ADs or not. In addition, MCI subgroups with heterogeneous functional states were examined in the context of different cognition decline trajectories. Five informative states were identified by feature selection, mainly involving functional connectivity belonging to the default mode network and working memory network. The classifiers discriminating AD and NC achieved the mean area under the receiver operating characteristic curve of 0.87 with leave-one-site-out cross-validation. Alterations in connectivity strength, fluctuation, and inter-synchronization were found in AD and MCIs. Moreover, individuals with MCI were clustered into two subgroups, which had different degrees of atrophy and different trajectories of cognition decline progression. The present study uncovered the alteration of dynamic functional connectivity in AD and highlighted that the dynamic states could be powerful features to discriminate patients from NCs. Furthermore, it demonstrated that these states help to identify MCIs with faster cognition decline and might contribute to the early prevention of AD.

RevDate: 2023-03-29

Gonzalez J, Wilson A, Byrd D, et al (2023)

Neuronal accumulation of hyperphosphorylated tau protein predicts stable memory impairment in people living with HIV.

AIDS (London, England) pii:00002030-990000000-00232 [Epub ahead of print].

OBJECTIVES: As lifespans increase in people with HIV (PWH), there is concern that age-related neurodegenerative disorders may contribute to cognitive decline. We asked whether brain accumulation of Alzheimer's disease (AD)-associated proteins amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) predicted cognitive performance in middle-aged PWH.

METHODS: In a prospectively followed, cognitively-characterized autopsy sample of 135 PWH, we used immunohistochemistry to assess Aβ plaques and neuronal p-tau in medial temporal and lateral frontal lobes. These pathologies were tested for associations with cognitive performance in 7 domains: motor, speed of information processing, working memory, memory encoding, memory retrieval, verbal fluency, and abstraction/executive function. Univariate and multivariate analyses accounting for HIV-associated variables, reading level, and comorbidities were conducted. Longitudinal trajectories of memory functions were evaluated in 60 individuals with a median follow-up of 6.0 years.

RESULTS: In this population with mean age 51.4 +/- 0.9 years, 58% displayed neuronal p-tau and 29% Aβ plaques. Neuronal p-tau, but not Aβ, predicted worse memory encoding and retrieval, but not other cognitive functions. With an ordinal hierarchy of neuronal p-tau locations (entorhinal, hippocampal, neocortical), decreased memory performance correlated with neocortical distribution. Memory function trajectories could not be distinguished between individuals with and without neuronal p-tau, and over 80% of the sample showed no change over time.

CONCLUSION: In this middle-aged sample, neuronal p-tau accumulation contributes to memory deficits, but is not associated with accelerated decline in function over time. In the absence of AD-like deterioration, other etiologies for neuronal p-tau in cognitively impaired PWH must be considered.

RevDate: 2023-03-29

Kwon HS, Kim JY, Koh SH, et al (2023)

Predicting cognitive stage transition using p-tau181, Centiloid, and other measures.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

BACKGROUND: A combination of plasma phospho-tau (p-tau), amyloid beta (Aβ)-positron emission tomography (PET), brain magnetic resonance imaging, cognitive function tests, and other biomarkers might predict future cognitive decline. This study aimed to investigate the efficacy of combining these biomarkers in predicting future cognitive stage transitions within 3 years.

METHODS: Among the participants in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE-V) study, 49 mild cognitive impairment (MCI) and 113 cognitively unimpaired (CU) participants with Aβ-PET and brain imaging data were analyzed.

RESULTS: Older age, increased plasma p-tau181, Aβ-PET positivity, and decreased semantic fluency were independently associated with cognitive stage transitions. Combining age, p-tau181, the Centiloid scale, semantic fluency, and hippocampal volume produced high predictive value in predicting future cognitive stage transition (area under the curve = 0.879).

CONCLUSIONS: Plasma p-tau181 and Centiloid scale alone or in combination with other biomarkers, might predict future cognitive stage transition in non-dementia patients.

HIGHLIGHTS: -Plasma p-tau181 and Centiloid scale might predict future cognitive stage transition. -Combining them or adding other biomarkers increased the predictive value. -Factors that independently associated with cognitive stage transition were demonstrated.

RevDate: 2023-03-29

Wadie CM, Ali RH, Mohamed AEA, et al (2023)

A comparative study of acetyl-l-carnitine and caloric restriction impact on hippocampal autophagy, apoptosis, neurogenesis, and astroglial function in AlCl3-induced Alzheimer's in rats.

Canadian journal of physiology and pharmacology [Epub ahead of print].

Alzheimer's disease (AD) is a worldwide chronic progressive neurodegenerative disease. We aimed to investigate and compare the neuroprotective impact of acetyl-l-carnitine and caloric restriction (CR) on AlCl3-induced AD to explore the pathogenesis and therapeutic strategies of AD. Sixty-seven adult male Wistar rats were allocated into Control, AlCl3, AlCl3-acetyl-l-carnitine, and AlCl3-CR groups. Each of AlCl3 and acetyl-l-carnitine were given by gavage in a daily dose of 100 mg/kg and CR was conducted by giving 70% of the daily average caloric intake of the control group. Rats were subjected to behavioral assessment using open field test, Y maze, novel object recognition test and passive avoidance test, biochemical assay of serum phosphorylated tau (pTau), hippocampal homogenate phosphorylated adenosine monophosphate-activated protein kinase, Beclin-1, Bcl-2-associated X protein, and B cell lymphoma 2 (Bcl2) as well as hippocampal Ki-67 and glial fibrillary acidic protein immunohistochemistry. AlCl3-induced cognitive and behavioral deficits coincident with impaired autophagy and enhanced apoptosis associated with defective neurogenesis and defective astrocyte activation. Acetyl-l-carnitine and CR partially protect against AlCl3-induced behavioral, cognitive, biochemical, and histological changes, with more ameliorative effect of acetyl-l-carnitine on hippocampal apoptotic markers, and more obvious behavioral and histological improvement with CR.

RevDate: 2023-03-29

Lovett RM, Benavente JY, Opsasnick LA, et al (2023)

Associations Between Cognitive Impairment Severity and Barriers to Healthcare Engagement Among Older Adults.

Journal of applied gerontology : the official journal of the Southern Gerontological Society [Epub ahead of print].

Objectives: To assess whether older adults with a cognitive impairment were more likely to report challenges interacting with medical providers, or to avoid needed medical care. Methods: Data for this exploratory, cross-sectional analysis were from older adults (N = 493) ages 60-82 participating in the "LitCog" cohort study. Multivariable generalized linear models compared cognitive impairment (none, mild, moderate, severe) with validated measures of healthcare engagement. Results: A moderate cognitive impairment was associated with delays in medical care due to embarrassment (RR 5.34.95% CI 1.30-22.0) and discomfort asking the doctor questions (RR 4.07, 95% CI 1.00-16.5). Conclusions: Intermediate cognitive deficits, such as with mild cognitive impairment (MCI) or mild dementias, may impact meaningful engagement with healthcare systems, potentially affecting timely detection and appropriate management of cognitive concerns and other chronic medical conditions. More research is needed to understand mechanisms underlying this relationship.

RevDate: 2023-03-29

Janelidze S, Barthélemy NR, He Y, et al (2023)

Mitigating the Associations of Kidney Dysfunction With Blood Biomarkers of Alzheimer Disease by Using Phosphorylated Tau to Total Tau Ratios.

JAMA neurology pii:2803026 [Epub ahead of print].

IMPORTANCE: Chronic kidney disease (CKD) has been associated with increased plasma concentrations of phosphorylated tau (p-tau) 217 and p-tau181, which potentially decreases their usefulness in the diagnostic workup of Alzheimer disease (AD).

OBJECTIVE: To investigate associations of CKD with plasma ratios of p-tau217 and p-tau181 to the corresponding unphosphorylated peptides in AD.

This cross-sectional study included patients with mild cognitive impairment (cohort 1; enrollment in 2000-2005) and replication in cohort 2 from the Swedish BioFINDER-2 study, including both cognitively unimpaired individuals and those with cognitive impairment (enrollment in 2017-2022). All participants were from 2 memory clinics in Sweden and had plasma tau assessments and CKD status established within 6 months of plasma collection.

EXPOSURES: P-tau217 and p-tau181, unphosphorylated peptides (Tau212-221 and Tau181-190), and the ratios (pT217/T217 and pT181/T181) as well as estimated glomerular filtration rate (eGFR) as an indicator of CKD.

MAIN OUTCOMES AND MEASURES: Associations between plasma-soluble p-tau and CKD.

RESULTS: A total of 141 participants from cohort 1 (mean [SD] age, 72.2 [7.7] years; 82 [58.2%] women) and 332 participants from cohort 2 (172 with cognitive impairment and 160 cognitively unimpaired individuals; mean [SD] age, 69.8 [9.4] years; 169 [50.9%] women) were included. Higher eGFR was associated with increased levels of plasma p-tau217, p-tau181, Tau212-221, and Tau181-190 in individuals with cognitive impairment (cohort 1: R range, -0.24 to -0.59; P < .004; cohort 2: R range, -0.18 to -0.53; P < .02) and cognitively unimpaired individuals (cohort 2: R range, -0.44 to -0.50; P < .001). However, eGFR did not correlate with the pT217/T217 ratio in patients with cognitive impairment (cohort 1: R, -0.11; P = .19; cohort 2: R, -0.02; P = .78), and the correlations with pT217/T217 ratio were significantly attenuated in cognitively unimpaired individuals (difference: R, -0.14 [95% CI, -0.22 to -0.007]; P = .001). For p-tau217 and pT217/T217, the mean fold increases in amyloid-β positive (Aβ+) compared with Aβ- groups ranged from 2.31 (95% CI, 1.86-2.77) to 4.61 (95% CI, 3.39-5.83) in participants with cognitive impairment and from 1.26 (95% CI, 0.98-1.55) to 1.27 (95% CI, 0.94-1.59) in cognitively unimpaired individuals and were clearly higher than the mean fold increases in those with CKD compared with those without CKD, ranging from 0.05 (95% CI, -0.28 to 0.38) to 0.72 (95% CI, 0.25-1.19) in participants with cognitive impairment and from 0.09 (95% CI, -0.08 to 0.26) to 0.36 (95% CI, 0.19-0.52) in cognitively unimpaired individuals.

CONCLUSIONS AND RELEVANCE: In this study, CKD was associated with increased plasma levels of soluble tau, but for p-tau217 the associations were considerably lower than the association with Aβ positivity. Importantly, the ratios, and especially pT217/T217, were less associated with CKD than p-tau forms alone and therefore are likely to more accurately reflect AD-related pathological changes.

RevDate: 2023-03-29

Wu N, Yao M, Xiao W, et al (2023)

Modular Pathway Compartmentalization for Agroclavine Overproduction in Saccharomyces cerevisiae.

ACS synthetic biology [Epub ahead of print].

Agroclavine, which has anti-depressant activity and anti-Alzheimer effects, is the raw material used to synthesize ergo-based drugs. Although the production of agroclavine from Saccharomyces cerevisiae is possible, its yield is exceptionally low. The current study proposes a modular compartmentalization strategy for identifying and modifying the bottleneck step in agroclavine overproduction. The agroclavine synthetic pathway was reconstituted in yeast, and the best combination of Claviceps fusiformis EasA with Claviceps purpurea EasD/EasG was identified. According to the data on the expression and subcellular localization of agroclavine pathway proteins, the whole pathway was divided into two modules by chanoclavine-I. Separate enzyme distribution within the downstream module and low expression of DmaW and EasE in the upstream module were identified as the bottleneck steps in the pathway. The pathway efficiency was enhanced 2.06-fold when the downstream module was entirely anchored to the endoplasmic reticulum compartment. Increasing NADPH supply by overexpressing POS5 further improved the agroclavine yield by 27.4%. Altering the intracellular localization of DmaW from the peroxisome to the endoplasmic reticulum (ER) not only improved protein expression but also accelerated the accumulation of agroclavine by 59.9%. Integration of all modified modules into the host chromosome resulted in an improved yield of agroclavine at 101.6 mg/L with flask fermentation (a 241-fold improvement over the initial strain) and ultimately produced 152.8 mg/L of agroclavine on fed-batch fermentation. The current study unlocked the potential of S. cerevisiae in the advanced biosynthesis of ergot alkaloids. It also provides a promising strategy to reconstitute compartmentalized pathways.

RevDate: 2023-03-29

Ahmad S, Alrouji M, Alhajlah S, et al (2023)

Secondary Metabolite Profiling, Antioxidant, Antidiabetic and Neuroprotective Activity of Cestrum nocturnum (Night Scented-Jasmine): Use of In Vitro and In Silico Approach in Determining the Potential Bioactive Compound.

Plants (Basel, Switzerland), 12(6): pii:plants12061206.

This study aims to describe the therapeutic potential of C. nocturnum leaf extracts against diabetes and neurological disorders via the targeting of α-amylase and acetylcholinesterase (AChE) activities, followed by computational molecular docking studies to establish a strong rationale behind the α-amylase and AChE inhibitory potential of C. nocturnum leaves-derived secondary metabolites. In our study, the antioxidant activity of the sequentially extracted C. nocturnum leaves extract was also investigated, in which the methanolic fraction exhibited the strongest antioxidant potential against DPPH (IC50 39.12 ± 0.53 µg/mL) and ABTS (IC50 20.94 ± 0.82 µg/mL) radicals. This extract strongly inhibited the α-amylase (IC50188.77 ± 1.67 µg/mL) and AChE (IC50 239.44 ± 0.93 µg/mL) in a non-competitive and competitive manner, respectively. Furthermore, in silico analysis of compounds identified in the methanolic extract of the leaves of C. nocturnum using GC-MS revealed high-affinity binding of these compounds with the catalytic sites of α-amylase and AChE, with binding energy ranging from -3.10 to -6.23 kcal/mol and from -3.32 to -8.76 kcal/mol, respectively. Conclusively, the antioxidant, antidiabetic, and anti-Alzheimer activity of this extract might be driven by the synergistic effect of these bioactive phytoconstituents.

RevDate: 2023-03-29

García-Lluch G, Peña-Bautista C, Royo LM, et al (2023)

Angiotensin II Receptor Blockers Reduce Tau/Aß42 Ratio: A Cerebrospinal Fluid Biomarkers' Case-Control Study.

Pharmaceutics, 15(3): pii:pharmaceutics15030924.

(1) Background: The role of antihypertensives in Alzheimer's Disease (AD) prevention is controversial. This case-control study aims to assess whether antihypertensive medication has a protective role by studying its association with amyloid and tau abnormal levels. Furthermore, it suggests a holistic view of the involved pathways between renin-angiotensin drugs and the tau/amyloidß42 ratio (tau/Aß42 ratio); (2) Methods: The medical records of the participant patients were reviewed, with a focus on prescribed antihypertensive drugs and clinical variables, such as arterial blood pressure. The Anatomical Therapeutic Chemical classification was used to classify each drug. The patients were divided into two groups: patients with AD diagnosis (cases) and cognitively healthy patients (control); (3) Results: Age and high systolic blood pressure are associated with a higher risk of developing AD. In addition, combinations of angiotensin II receptor blockers are associated with a 30% lower t-tau/Aß42 ratio than plain angiotensin-converting enzyme inhibitor consumption; (4) Conclusions: Angiotensin II receptor blockers may play a potential role in neuroprotection and AD prevention. Likewise, several mechanisms, such as the PI3K/Akt/GSK3ß or the ACE1/AngII/AT1R axis, may link cardiovascular pathologies and AD presence, making its modulation a pivotal point in AD prevention. The present work highlights the central pathways in which antihypertensives may affect the presence of pathological amyloid and tau hyperphosphorylation.

RevDate: 2023-03-29

Ailioaie LM, Ailioaie C, G Litscher (2023)

Photobiomodulation in Alzheimer's Disease-A Complementary Method to State-of-the-Art Pharmaceutical Formulations and Nanomedicine?.

Pharmaceutics, 15(3): pii:pharmaceutics15030916.

Alzheimer's disease (AD), as a neurodegenerative disorder, usually develops slowly but gradually worsens. It accounts for approximately 70% of dementia cases worldwide, and is recognized by WHO as a public health priority. Being a multifactorial disease, the origins of AD are not satisfactorily understood. Despite huge medical expenditures and attempts to discover new pharmaceuticals or nanomedicines in recent years, there is no cure for AD and not many successful treatments are available. The current review supports introspection on the latest scientific results from the specialized literature regarding the molecular and cellular mechanisms of brain photobiomodulation, as a complementary method with implications in AD. State-of-the-art pharmaceutical formulations, development of new nanoscale materials, bionanoformulations in current applications and perspectives in AD are highlighted. Another goal of this review was to discover and to speed transition to completely new paradigms for the multi-target management of AD, to facilitate brain remodeling through new therapeutic models and high-tech medical applications with light or lasers in the integrative nanomedicine of the future. In conclusion, new insights from this interdisciplinary approach, including the latest results from photobiomodulation (PBM) applied in human clinical trials, combined with the latest nanoscale drug delivery systems to easily overcome protective brain barriers, could open new avenues to rejuvenate our central nervous system, the most fascinating and complex organ. Picosecond transcranial laser stimulation could be successfully used to cross the blood-brain barrier together with the latest nanotechnologies, nanomedicines and drug delivery systems in AD therapy. Original, smart and targeted multifunctional solutions and new nanodrugs may soon be developed to treat AD.

RevDate: 2023-03-29

Arbez-Gindre C, Steele BR, M Micha-Screttas (2023)

Dendrimers in Alzheimer's Disease: Recent Approaches in Multi-Targeting Strategies.

Pharmaceutics, 15(3): pii:pharmaceutics15030898.

Nanomaterials play an increasingly important role in current medicinal practice. As one of the most significant causes of human mortality, and one that is increasing year by year, Alzheimer's disease (AD) has been the subject of a very great body of research and is an area in which nanomedicinal approaches show great promise. Dendrimers are a class of multivalent nanomaterials which can accommodate a wide range of modifications that enable them to be used as drug delivery systems. By means of suitable design, they can incorporate multiple functionalities to enable transport across the blood-brain barrier and subsequently target the diseased areas of the brain. In addition, a number of dendrimers by themselves often display therapeutic potential for AD. In this review, the various hypotheses relating to the development of AD and the proposed therapeutic interventions involving dendrimer-base systems are outlined. Special attention is focused on more recent results and on the importance of aspects such as oxidative stress, neuroinflammation and mitochondrial dysfunction in approaches to the design of new treatments.

RevDate: 2023-03-29

Ravetti S, Garro AG, Gaitán A, et al (2023)

Naringin: Nanotechnological Strategies for Potential Pharmaceutical Applications.

Pharmaceutics, 15(3): pii:pharmaceutics15030863.

Polyphenols comprise a number of natural substances, such as flavonoids, that show interesting biological effects. Among these substances is naringin, a naturally occurring flavanone glycoside found in citrus fruits and Chinese medicinal herbs. Several studies have shown that naringin has numerous biological properties, including cardioprotective, cholesterol-lowering, anti-Alzheimer's, nephroprotective, antiageing, antihyperglycemic, antiosteoporotic and gastroprotective, anti-inflammatory, antioxidant, antiapoptotic, anticancer and antiulcer effects. Despite its multiple benefits, the clinical application of naringin is severely restricted due to its susceptibility to oxidation, poor water solubility, and dissolution rate. In addition, naringin shows instability at acidic pH, is enzymatically metabolized by β-glycosidase in the stomach and is degraded in the bloodstream when administered intravenously. These limitations, however, have been overcome thanks to the development of naringin nanoformulations. This review summarizes recent research carried out on strategies designed to improve naringin's bioactivity for potential therapeutic applications.

RevDate: 2023-03-29

Georgieva D, Nikolova D, Vassileva E, et al (2023)

Chitosan-Based Nanoparticles for Targeted Nasal Galantamine Delivery as a Promising Tool in Alzheimer's Disease Therapy.

Pharmaceutics, 15(3): pii:pharmaceutics15030829.

Natural alkaloid galantamine is widely used for the treatment of mild to moderate Alzheimer's dementia. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solutions. However, its oral delivery can cause some unwanted side effects, such as gastrointestinal disturbances, nausea, and vomiting. Intranasal administration is one possible way to avoid such unwanted effects. In this work, chitosan-based nanoparticles (NPs) were studied as potential GH delivery vehicles for nasal application. The NPs were synthesized via ionic gelation and studied using dynamic light scattering (DLS) as well as by spectroscopic and thermal methods. The GH-loaded chitosan-alginate complex particles were also prepared as a way to modify the release of GH. The high loading efficiency of the GH was confirmed for both types of particles, at 67% for the GH-loaded chitosan NPs and 70% for the complex chitosan/alginate GH-loaded particles. The mean particle size of the GH-loaded chitosan NPs was about 240 nm, while the sodium alginate coated chitosan particles loaded with GH were expectedly bigger, with a mean particle size of ~286 nm. GH release profiles in PBS at 37 °C were obtained for both types of NPs, and it was found that the GH-loaded chitosan NPs allowed the prolonged release of the incorporated drug for a period of 8 h, while the complex GH-loaded chitosan/alginate NPs released the incorporated GH faster. The stability of the prepared GH-loaded NPs was also demonstrated after 1 year of storage at 5 °C ± 3 °C.

RevDate: 2023-03-29

Aytac S, Gundogdu O, Bingol Z, et al (2023)

Synthesis of Schiff Bases Containing Phenol Rings and Investigation of Their Antioxidant Capacity, Anticholinesterase, Butyrylcholinesterase, and Carbonic Anhydrase Inhibition Properties.

Pharmaceutics, 15(3): pii:pharmaceutics15030779.

The widespread usage of Schiff bases in chemistry, industry, medicine, and pharmacy has increased interest in these compounds. Schiff bases and derivative compounds have important bioactive properties. Heterocyclic compounds containing phenol derivative groups in their structure have the potential to capture free radicals that can cause diseases. In this study, we designed and synthesized eight Schiff bases (10-15) and hydrazineylidene derivatives (16-17), which contain phenol moieties and have the potential to be used as synthetic antioxidants, for the first time using microwave energy. Additionally, the antioxidant effects of Schiff bases (10-15) and hydrazineylidene derivatives (16-17) were studied using by the bioanalytical methods of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical (ABTS[•+]) and 1,1-diphenyl-2-picrylhydrazyl (DPPH[•]) scavenging activities, and Fe[3+], Cu[2+], and Fe[3+]-TPTZ complex reducing capacities. In the context of studies on antioxidants, Schiff bases (10-15) and hydrazineylidene derivatives (16-17) were found to be as powerful DPPH (IC50: 12.15-99.01 μg/mL) and ABTS[•+] (IC50: 4.30-34.65 μg/mL). Additionally, the inhibition abilities of Schiff bases (10-15) and hydrazineylidene derivatives (16-17) were determined towards some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCAs I and II), enzymes that are linked to some global disorders including Alzheimer's disease (AD), epilepsy, and glaucoma. In the context of studies on enzyme inhibition, it was observed that the synthesized Schiff bases (10-15) and hydrazineylidene derivatives (16-17) inhibited AChE, BChE, hCAs I, and hCA II enzymes with IC50 values in ranges of 16.11-57.75 nM, 19.80-53.31 nM, 26.08 ± 8.53 nM, and 85.79 ± 24.80 nM, respectively. In addition, in light of the results obtained, we hope that this study will be useful and guiding for the evaluation of biological activities in the fields of the food, medical, and pharmaceutical industries in the future.

RevDate: 2023-03-29

Araldi GL, YW Hwang (2023)

Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson's Disease.

Pharmaceuticals (Basel, Switzerland), 16(3): pii:ph16030443.

Natural polyphenol derivatives such as those found in green tea have been known for a long time for their useful therapeutic activity. Starting from EGCG, we have discovered a new fluorinated polyphenol derivative (1c) characterized by improved inhibitory activity against DYRK1A/B enzymes and by considerably improved bioavailability and selectivity. DYRK1A is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome and Alzheimer's disease), oncology, and type 2 diabetes (pancreatic β-cell expansion). Systematic structure-activity relationship (SAR) on trans-GCG led to the discovery that the introduction of a fluoro atom in the D ring and methylation of the hydroxy group from para to the fluoro atom provide a molecule (1c) with more desirable drug-like properties. Owing to its good ADMET properties, compound 1c showed excellent activity in two in vivo models, namely the lipopolysaccharide (LPS)-induced inflammation model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model for Parkinson's disease.

RevDate: 2023-03-29

Ono H, Nishijima Y, S Ohta (2023)

Therapeutic Inhalation of Hydrogen Gas for Alzheimer's Disease Patients and Subsequent Long-Term Follow-Up as a Disease-Modifying Treatment: An Open Label Pilot Study.

Pharmaceuticals (Basel, Switzerland), 16(3): pii:ph16030434.

(1) Background: Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for AD through multifactorial mechanisms, an open label pilot study on H2 treatment was conducted. (2) Methods: Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus. (3) Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (-4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly). (4) Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects, despite its limitations.

RevDate: 2023-03-29

Farn SS, Cheng KH, Huang YR, et al (2023)

Automated Synthesis of [[18]F]Flumazenil Application in GABAA Receptor Neuroimaging Availability for Rat Model of Anxiety.

Pharmaceuticals (Basel, Switzerland), 16(3): pii:ph16030417.

Clinical studies have demonstrated that the γ-aminobutyric acid type A (GABAA) receptor complex plays a central role in the modulation of anxiety. Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels. The radioactive GABA/BZR receptor antagonist, fluorine-18-labeled flumazenil, [[18]F]flumazenil, behaves as a potential PET imaging agent for the evaluation of cortical damage of the brain in stroke, alcoholism, and for Alzheimer disease investigation. The main goal of our study was to investigate a fully automated nucleophilic fluorination system, with solid extraction purification, developed to replace traditional preparation methods, and to detect underlying expressions of contextual fear and characterize the distribution of GABAA receptors in fear-conditioned rats by [[18]F]flumazenil. A carrier-free nucleophilic fluorination method using an automatic synthesizer with direct labeling of a nitro-flumazenil precursor was implemented. The semi-preparative high-performance liquid chromatography (HPLC) purification method (RCY = 15-20%) was applied to obtain high purity [[18]F]flumazenil. Nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging and ex vivo autoradiography were used to analyze the fear conditioning of rats trained with 1-10 tone-foot-shock pairings. The anxiety rats had a significantly lower cerebral accumulation (in the amygdala, prefrontal cortex, cortex, and hippocampus) of fear conditioning. Our rat autoradiography results also supported the findings of PET imaging. Key findings were obtained by developing straightforward labeling and purification procedures that can be easily adapted to commercially available modules for the high radiochemical purity of [[18]F]flumazenil. The use of an automatic synthesizer with semi-preparative HPLC purification would be a suitable reference method for new drug studies of GABAA/BZR receptors in the future.

RevDate: 2023-03-29

Laivut S, Moongkarndi P, Kitphati W, et al (2023)

Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities.

Pharmaceuticals (Basel, Switzerland), 16(3): pii:ph16030355.

In this investigation, a number of phenoxyindole derivatives were designed, synthesized, and tested for their neuroprotective ability on SK-N-SH cells against Aβ42-induced cell death and biologically specific activities involved in anti-Aβ aggregation, anti-AChE, and antioxidant effects. The proposed compounds, except compounds 9 and 10, could protect SK-N-SH cells at the IC50 of anti-Aβ aggregation with cell viability values ranging from 63.05% ± 2.70% to 87.90% ± 3.26%. Compounds 3, 5, and 8 demonstrated striking relationships between the %viability of SK-N-SH cells and IC50 values of anti-Aβ aggregation and antioxidants. No significant potency of all synthesized compounds against AChE was found. Among them, compound 5 showed the strongest anti-Aβ and antioxidant properties with IC50 values of 3.18 ± 0.87 and 28.18 ± 1.40 μM, respectively. The docking data on the monomeric Aβ peptide of compound 5 demonstrated good binding at regions involved in the aggregation process, and the structural feature made it possible to be a superior radical scavenger. The most effective neuroprotectant belonged to compound 8, with a cell viability value of 87.90% ± 3.26%. Its unique mechanisms for enhancing the protective impact may serve additional purposes since it demonstrated mild biological-specific effects. In silico prediction of CNS penetration shows strong passive penetration ability across the blood-brain barrier from blood vessels to the CNS for compound 8. In light of our findings, compounds 5 and 8 appeared as potentially intriguing lead compounds for new therapeutic approaches to Alzheimer's disease. More in vivo testing will be revealed in due course.

RevDate: 2023-03-29

Al-Tawarah NM, Al-Dmour RH, Abu Hajleh MN, et al (2023)

Rosmarinus officinalis and Mentha piperita Oils Supplementation Enhances Memory in a Rat Model of Scopolamine-Induced Alzheimer's Disease-like Condition.

Nutrients, 15(6): pii:nu15061547.

Alzheimer's disease is regarded as a common neurodegenerative disease that may lead to dementia and the loss of memory. We report here the nootropic and anti-amnesic effects of both peppermint and rosemary oils using a rat model of scopolamine-induced amnesia-like AD. Rats were administered orally with two doses (50 and 100 mg/kg) of each single oil and combined oils. The positive group used donepezil (1 mg/kg). In the therapeutic phase, rats were administered scopolamine (1 mg/kg) through the oral administration of oils. During the nootropic phase, both oils showed a significant (p < 0.05) decrease in radial arm maze latency times, working memory, and reference memory errors compared with the normal group, along with significant (p < 0.05) enhancements of long-term memory during the passive avoidance test. Therapeutic phase results revealed significant enhancements of memory processing compared with the positive groups. In the hippocampus, oils exhibited an elevation of BDNF levels in a dose-dependent manner. Immunohistochemistry findings showed increased hippocampal neurogenesis suppressed by scopolamine in the sub-granular zone, and the anti-amnesic activity of single oil was enhanced when the two oils combined. Gas chromatography-mass spectrometry (GCMS) of the two oils revealed sufficient compounds (1,8-Cineole, α-Pinene, menthol and menthone) with potential efficacy in the memory process and cognitive defects. Our work suggests that both oils could enhance the performance of working and spatial memory, and when combined, more anti-amnesic activity was produced. A potential enhancement of hippocampal growth and neural plasticity was apparent with possible therapeutic activity to boost memory in AD patients.

RevDate: 2023-03-29

Ogawa T, Sawane K, Ookoshi K, et al (2023)

Supplementation with Flaxseed Oil Rich in Alpha-Linolenic Acid Improves Verbal Fluency in Healthy Older Adults.

Nutrients, 15(6): pii:nu15061499.

The effects of docosahexaenoic acid supplements on cognitive function have long been demonstrated, but the effects of alpha-linolenic acid, a precursor of docosahexaenoic acid, have not been fully tested. The search for functional foods that delay cognitive decline in the older adults is considered a very important area from a preventive perspective. The aim of this study was to conduct an exploratory evaluation of alpha-linolenic acid on various cognitive functions in healthy older subjects. Sixty healthy older adults aged 65 to 80 years, living in Miyagi prefecture, without cognitive impairment or depression, were included in the randomized, double-blinded, placebo-controlled clinical trial. Study subjects were randomly divided into two groups and received either 3.7 g/day of flaxseed oil containing 2.2 g of alpha-linolenic acid, or an isocaloric placebo (corn oil) containing 0.04 g of alpha-linolenic acid for 12 weeks. The primary endpoints were six cognitive functions closely related to everyday life: attention and concentration, executive function, perceptual reasoning, working memory, processing speed and memory function. After 12 weeks of intake, changes in verbal fluency scores on the frontal assessment battery at bedside, a neuropsychological test assessing executive function, in which participants are asked to answer as many words as possible in Japanese, were significantly greater in the intervention group (0.30 ± 0.53) than in the control group (0.03 ± 0.49, p < 0.05). All other cognitive test scores were not significantly different between the groups. In conclusion, daily consumption of flaxseed oil containing 2.2 g alpha-linolenic acid improved cognitive function, specifically verbal fluency, despite the age-related decline, in healthy individuals with no cognitive abnormalities. Further validation studies focusing on the effects of alpha-linolenic acid on verbal fluency and executive function in older adults are needed, as verbal fluency is a predictor of Alzheimer's disease development, important for cognitive health.

RevDate: 2023-03-29

Griebsch LV, Theiss EL, Janitschke D, et al (2023)

Aspartame and Its Metabolites Cause Oxidative Stress and Mitochondrial and Lipid Alterations in SH-SY5Y Cells.

Nutrients, 15(6): pii:nu15061467.

Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes, synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible uncertainties regarding aspartame's ability to induce oxidative stress, amongst others, has led to the recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative diseases such as Alzheimer's disease. In the present study, treatment of the human neuroblastoma cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine, and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract, resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1, and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should be addressed in vivo.

RevDate: 2023-03-29

Kurowska A, Ziemichód W, Herbet M, et al (2023)

The Role of Diet as a Modulator of the Inflammatory Process in the Neurological Diseases.

Nutrients, 15(6): pii:nu15061436.

Neurological diseases are recognized as major causes of disability and mortality worldwide. Due to the dynamic progress of diseases such as Alzheimer's disease (AD), Parkinson's Disease (PD), Schizophrenia, Depression, and Multiple Sclerosis (MD), scientists are mobilized to look for new and more effective methods of interventions. A growing body of evidence suggests that inflammatory processes and an imbalance in the composition and function of the gut microbiome, which play a critical role in the pathogenesis of various neurological diseases and dietary interventions, such as the Mediterranean diet the DASH diet, or the ketogenic diet can have beneficial effects on their course. The aim of this review was to take a closer look at the role of diet and its ingredients in modulating inflammation associated with the development and/or progression of central nervous system diseases. Presented data shows that consuming a diet abundant in fruits, vegetables, nuts, herbs, spices, and legumes that are sources of anti-inflammatory elements such as omega-3 fatty acids, polyphenols, vitamins, essential minerals, and probiotics while avoiding foods that promote inflammation, create a positive brain environment and is associated with a reduced risk of neurological diseases. Personalized nutritional interventions may constitute a non-invasive and effective strategy in combating neurological disorders.

RevDate: 2023-03-29

Currenti W, Godos J, Alanazi AM, et al (2023)

Dietary Fats and Cognitive Status in Italian Middle-Old Adults.

Nutrients, 15(6): pii:nu15061429.

UNLABELLED: The increase in life expectancy led to a significant rise in the prevalence of age-related neurological diseases, such as cognitive impairment, dementia, and Alzheimer's disease. Although genetics certainly play a role, nutrition emerged as a key factor in maintaining optimal cognitive function among older adults. Therefore, the study aimed to investigate whether specific categories and subcategories of dietary fats, based on carbon-chain length, are associated with cognitive status in a cohort of 883 Italian participants over the age of 50.

METHODS: The intake of total, single class of dietary fat, such as saturated fatty acids (SFA), monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA), and also single fatty acids grouped according to carbon-chain length, were evaluated by food frequency questionnaires (FFQs). Cognitive health was assessed using the short portable mental status questionnaire (SPMSQ).

RESULTS: After adjustment for potential confounding factors subjects with a moderate consumption of both short-chain SFA (for Q2 vs. Q1, OR = 0.23, 95% CI: 0.08, 0.66) and middle-chain SFA specifically lauric acid (C12:0) intake (for Q2 vs. Q1, OR = 0.27, 95% CI: 0.09, 0.77) were less likely to suffer from cognitive impairment. Among single MUFAs, erucic acid (C22:1) intake resulted in an inverse association, in a linear way, with cognitive impairment (for Q4 vs. Q1, OR = 0.04, 95% CI: 0.00, 0.39). Conversely, moderate intake of linoleic acid (C18:2) was associated with cognitive impairment (Q3 vs. Q1, OR = 4.59, 95% CI: 1.51, 13.94). Regarding other PUFAs, individuals consuming moderate intake alpha linolenic acid (C18:3) were less likely to have cognitive impairment (for Q3 vs. Q1, OR = 0.19, 95% CI: 0.06, 0.64).

CONCLUSIONS: Total SFA intake appeared to be inversely associated with cognitive impairment. Regarding specific subtypes of fatty acids, the results mostly referred to short- and middle-chain SFA. Further studies are needed to validate the results of the present study.

RevDate: 2023-03-29

Zhai X, Wang K, Gao X, et al (2023)

Research Progress on Chemical Constituents and Pharmacological Activities of Menispermi Rhizoma.

Molecules (Basel, Switzerland), 28(6): pii:molecules28062701.

Menispermi Rhizoma, the rhizome of Menispermum dauricum DC., is a traditional Chinese medicine, which has the effect of clearing away heat and detoxification, dispelling wind, and relieving pain. It is often used in the treatment of sore throat, enteritis, dysentery, and rheumatism. The chemical constituents of M. Rhizoma mainly include alkaloids, phenolic acids, quinones, cardiotonic glycosides, and so on. Modern pharmacological studies have proved that M. Rhizoma has the effects of anti-tumour, anti-inflammation, anti-oxidation, bacteriostasis, cardio-cerebrovascular protection, anti-depression and anti-Alzheimer's disease. In recent years, the chemical constituents of M. Rhizoma have been found continuously, and the pharmacological studies have deepened gradually. This paper reviews the research progress on the chemical composition and pharmacological effects of M. Rhizoma, to provide a basis for further research and development of its medicinal value.

RevDate: 2023-03-29

El Hajj S, Canabady-Rochelle L, C Gaucher (2023)

Nature-Inspired Bioactive Compounds: A Promising Approach for Ferroptosis-Linked Human Diseases?.

Molecules (Basel, Switzerland), 28(6): pii:molecules28062636.

Ferroptosis is a type of cell death driven by iron overload and lipid peroxidation. It is considered a key mechanism in the development of various diseases such as atherosclerosis, Alzheimer, diabetes, cancer, and renal failure. The redox status of cells, such as the balance between intracellular oxidants (lipid peroxides, reactive oxygen species, free iron ions) and antioxidants (glutathione, glutathione Peroxidase 4), plays a major role in ferroptosis regulation and constitutes its principal biomarkers. Therefore, the induction and inhibition of ferroptosis are promising strategies for disease treatments such as cancer or neurodegenerative and cardiovascular diseases, respectively. Many drugs have been developed to exert ferroptosis-inducing and/or inhibiting reactions, such as erastin and iron-chelating compounds, respectively. In addition, many natural bioactive compounds have significantly contributed to regulating ferroptosis and ferroptosis-induced oxidative stress. Natural bioactive compounds are largely abundant in food and plants and have been for a long time, inspiring the development of various low-toxic therapeutic drugs. Currently, functional bioactive peptides are widely reported for their antioxidant properties and application in human disease treatment. The scientific evidence from biochemical and in vitro tests of these peptides strongly supports the existence of a relationship between their antioxidant properties (such as iron chelation) and ferroptosis regulation. In this review, we answer questions concerning ferroptosis milestones, its importance in physiopathology mechanisms, and its downstream regulatory mechanisms. We also address ferroptosis regulatory natural compounds as well as provide promising thoughts about bioactive peptides.

RevDate: 2023-03-29

Hamed AA, El-Shiekh RA, Mohamed OG, et al (2023)

Cholinesterase Inhibitors from an Endophytic Fungus Aspergillus niveus Fv-er401: Metabolomics, Isolation and Molecular Docking.

Molecules (Basel, Switzerland), 28(6): pii:molecules28062559.

Alzheimer's disease poses a global health concern with unmet demand requiring creative approaches to discover new medications. In this study, we investigated the chemical composition and the anticholinesterase activity of Aspergillus niveus Fv-er401 isolated from Foeniculum vulgare (Apiaceae) roots. Fifty-eight metabolites were identified using UHPLC-MS/MS analysis of the crude extract. The fungal extract showed acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects with IC50 53.44 ± 1.57 and 48.46 ± 0.41 µg/mL, respectively. Two known metabolites were isolated, terrequinone A and citrinin, showing moderate AChE and BuChE inhibitory activity using the Ellman's method (IC50 = 11.10 ± 0.38 µg/mL and 5.06 ± 0.15 µg/mL, respectively for AChE, and IC50 15.63 ± 1.27 µg/mL and 8.02 ± 0.08 µg/mL, respectively for BuChE). As evidenced by molecular docking, the isolated compounds and other structurally related metabolites identified by molecular networking had the required structural features for AChE and BuChE inhibition. Where varioxiranol G (-9.76 and -10.36 kcal/mol), penicitrinol B (-9.50 and -8.02 kcal/mol), dicitrinol A (-8.53 and -7.98 kcal/mol) and asterriquinone CT5 (-8.02 and -8.25 kcal/mol) showed better binding scores as AChE and BuChE inhibitors than the co-crystallized inhibitor (between -7.89 and 7.82 kcal/mol) making them promising candidates for the development of new drugs to treat Alzheimer's.

RevDate: 2023-03-29

Dawra M, Bouajila J, El Beyrouthy M, et al (2023)

Chemical Characterization and Antioxidant, Antibacterial, Antiacetylcholinesterase and Antiproliferation Properties of Salvia fruticosa Miller Extracts.

Molecules (Basel, Switzerland), 28(6): pii:molecules28062429.

The Salvia fruticosa (Mill.) is the most medicinal plant used in Lebanon. The aim of this study is to investigate the phytochemical composition and the biological activities (in vitro) of its extracts. The plant was extracted by cold maceration with four solvents presenting an increasing polarity: cyclohexane (CHX), dichloromethane (DCM), ethyl acetate (EtOAc) and methanol (MeOH). The extracts were screened for their chemical composition by a HPLC-DAD detector for phenolic compounds identification and quantification and by GC-MS for volatile compounds detection. The antioxidant capacity (DPPH inhibition) was tested. Biological activities, mainly anti-Alzheimer activity (acetylcholinesterase inhibition), the antiproliferation of two human colon cancer cell lines (HCT-116 and Caco-2 cells) and antibacterial activity, were evaluated. Ten aromatic compounds were quantified by HPLC-DAD analysis. A total of 123 compounds were detected by GC-MS analysis. The MeOH extract showed a very interesting antioxidant activity with an inhibition percentage (IP) of 76.1% and an IC50 of 19.4 μg/mL. The EtOAc extract exhibited the strongest inhibition against the acetylcholinesterase activity (IP = 60.6%) at 50 μg/mL. It also strongly inhibited the proliferation of the HCT-116 cells (IP = 87.5%), whereas the DCM extract gave the best result with the Caco-2 cells (IP = 72.3%). The best antibacterial activity was obtained with the MeOH extract against Staphylococcus aureus (MIC = 1.2 μg/mL) and with the EtOAc extract against Escherichia coli (MIC = 2.4 μg/mL). This study highlights the chemical composition and therapeutic potential of S. fruticosa. It is important to mention that the following chemical compounds were identified for the first time in plant extracts: 2,6,11,15-tetramethyl-hexadeca-2,6,8,10,14-pentaene; 4,5,6,7-tetrahydroxy-1,8,8,9-tetramethyl-8,9-dihydrophenaleno [1,2-b]furan-3-one; podocarpa-1,8,11,13-tetraen-3-one,14-isopropyl-1,13-dimethoxy; podocarpa-8,11,13-trien-3-one,12-hydroxy-13-isopropyl-,acetate; 3',8,8'-trimethoxy-3-piperidin-1-yl-2,2'-binaphthyl-1,1',4,4'-tetrone; and 2,3-dehydroferruginol, thus underlining the originality of this study.

RevDate: 2023-03-29

Bernier F, Kuhara T, J Xiao (2023)

Probiotic Bifidobacterium breve MCC1274 Protects against Oxidative Stress and Neuronal Lipid Droplet Formation via PLIN4 Gene Regulation.

Microorganisms, 11(3): pii:microorganisms11030791.

Consumption of Bifidobacterium breve MCC1274 has been shown to improve memory and prevent brain atrophy in populations with mild cognitive impairment (MCI). Preclinical in vivo studies using Alzheimer's disease (AD) models indicate that this probiotic protects against brain inflammation. There is growing evidence that lipid droplets are associated with brain inflammation, and lipid-associated proteins called perilipins could play an important role in neurodegenerative diseases such as dementia. In this study, we found that B. breve MCC1274 cell extracts significantly decreased the expression of perilipin 4 (PLIN4), which encodes a lipid droplet docking protein whose expression is known to be increased during inflammation in SH-SY5Y cells. Niacin, an MCC1274 cell extract component, increased PLIN4 expression by itself. Moreover, MCC1274 cell extracts and niacin blocked the PLIN4 induction caused by oxidative stress in SH-SY5Y cells, reduced lipid droplet formation, and prevented IL-6 cytokine production. These results offer a possible explanation for the effect of this strain on brain inflammation.

RevDate: 2023-03-29

El-Sayed H, Hamada MA, Elhenawy AA, et al (2023)

Acetylcholine Esterase Inhibitory Effect, Antimicrobial, Antioxidant, Metabolomic Profiling, and an In Silico Study of Non-Polar Extract of The Halotolerant Marine Fungus Penicillium chrysogenum MZ945518.

Microorganisms, 11(3): pii:microorganisms11030769.

Major health issues, such as the rise in oxidative stress, incidences of Alzheimer's disease, and infections caused by antibiotic-resistant microbes, have prompted researchers to look for new therapeutics. Microbial extracts are still a good source of novel compounds for biotechnological use. The objective of the current work was to investigate marine fungal bioactive compounds with potential antibacterial, antioxidant, and acetylcholinesterase inhibitory effects. Penicillium chrysogenum strain MZ945518 was isolated from the Mediterranean Sea in Egypt. The fungus was halotolerant with a salt tolerance index of 1.3. The mycelial extract showed antifungal properties against Fusarium solani with an inhibitory percentage of 77.5 ± 0.3, followed by Rhizoctonia solani and Fusarium oxysporum with percentages of 52 ± 0.0 and 40 ± 0.5, respectively. The extract also showed antibacterial activity against both Gram-negative and Gram-positive bacterial strains using the agar diffusion technique. The fungal extract was significantly more effective with Proteus mirabilis ATCC 29906 and Micrococcus luteus ATCC 9341; inhibition zones recorded 20 and 12 mm, respectively, compared with the antibiotic gentamycin, which recorded 12 and 10 mm, respectively. The antioxidant activity of the fungus extract revealed that it successfully scavenged DPPH free radicals and recorded an IC50 of 542.5 µg/mL. Additionally, it was capable of reducing Fe[3+] to Fe[2+] and exhibiting chelating ability in the metal ion-chelating test. The fungal extract was identified as a crucial inhibitor of acetylcholinesterase with an inhibition percentage of 63% and an IC50 value of 60.87 µg/mL. Using gas chromatography-mass spectrometry (GC/MS), 20 metabolites were detected. The most prevalent ones were (Z)-18-octadec-9-enolide and 1,2-Benzenedicarboxylic acid, with ratios of 36.28 and 26.73%, respectively. An in silico study using molecular docking demonstrated interactions between the major metabolites and the target proteins, including: DNA Gyrase, glutathione S-transferase, and Acetylcholinesterase, confirming the extract's antimicrobial and antioxidant activity. Penicillium chrysogenum MZ945518, a halotolerant strain, has promising bioactive compounds with antibacterial, antioxidant, and acetylcholinesterase inhibitory activities.

RevDate: 2023-03-29

Knight E, Geetha T, Broderick TL, et al (2023)

The Role of Dietary Antioxidants and Their Potential Mechanisms in Alzheimer's Disease Treatment.

Metabolites, 13(3): pii:metabo13030438.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and characterized by amyloid-β plaques and neurofibrillary tau tangles. Although AD's exact pathophysiology remains unclear, oxidative stress is known to play a role in the neurodegenerative process. Since no curative treatment exists, antioxidants represent a potential treatment for AD due to their ability to modulate oxidative stress. Therefore, this review aims to examine the impact of antioxidant supplementation and its potential mechanisms on cognitive function. The review primarily discusses research articles published between 2012 and 2022 reporting the results of clinical trials involving antioxidant supplementation on cognitive function in individuals with AD. Antioxidant supplementation included probiotics, selenium, melatonin, resveratrol, rosmarinic acid, carotenoids, curcumin, vitamin E, and coenzyme Q. While the studies included in this review did not provide much evidence for the beneficial role of antioxidant supplements on cognitive function in AD, the results varied from antioxidant to antioxidant and among trials examining the same antioxidant. Furthermore, many of the studies' findings face several limitations, including short trial durations, small sample sizes, and a lack of diversity among study participants. As a result, more research is required to examine the impact of antioxidant supplementation on cognitive function in AD.

RevDate: 2023-03-29

Costello SM, Cheney AM, Waldum A, et al (2023)

A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations.

Metabolites, 13(3): pii:metabo13030433.

Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer's (AD) and Parkinson's (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut-brain axis of FD. Here, [1]H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut-brain-metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.

RevDate: 2023-03-29

Chear NJ, Ching-Ga TAF, Khaw KY, et al (2023)

Natural Corynanthe-Type Cholinesterase Inhibitors from Malaysian Uncaria attenuata Korth.: Isolation, Characterization, In Vitro and In Silico Studies.

Metabolites, 13(3): pii:metabo13030390.

The Uncaria genus is notable for its therapeutic potential in treating age-related dementia, such as Alzheimer's disease. A phytochemical study of the leaves of Malaysian Uncaria attenuata Korth., afforded an undescribed natural corynanthe-type oxindole alkaloid, isovillocarine D (1) together with two known indole alkaloids, villocarine A (2) and geissoschizine methyl ether (3), and their structural identification was performed with extensive mono- and bidimensional NMR and MS spectroscopic methods. The isolated alkaloids were evaluated for their acetylcholinesterase (AChE)- and butyrylcholinesterase (BChE)-inhibitory activity. The results indicated that compound (2) was the most potent inhibitor against both AChE and BChE, with IC50 values of 14.45 and 13.95 µM, respectively, whereas compounds (1) and (3) were selective BChE inhibitors with IC50 values of 35.28 and 17.65 µM, respectively. In addition, molecular docking studies revealed that compound (2) interacts with the five main regions of AChE via both hydrogen and hydrophobic bonding. In contrast to AChE, the interactions of (2) with the enzymatic site of BChE are established only through hydrophobic bonding. The current finding suggests that U. attenuata could be a good source of bioactive alkaloids for treating age-related dementia.

RevDate: 2023-03-29

Maszka P, Kwasniak-Butowska M, Cysewski D, et al (2023)

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy.

Metabolites, 13(3): pii:metabo13030369.

The prevalence of neurodegenerative diseases (NDs) is increasing due to the aging population and improved longevity. They are characterized by a range of pathological hallmarks, including protein aggregation, mitochondrial dysfunction, and oxidative stress. The aim of this review is to summarize the alterations in brain energy and amino acid metabolism in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Based on our findings, we proposed a group of selected metabolites related to disturbed energy or mitochondrial metabolism as potential indicators or predictors of disease. We also discussed the hidden challenges of metabolomics studies in NDs and proposed future directions in this field. We concluded that biochemical parameters of brain energy metabolism disruption (obtained with metabolomics) may have potential application as a diagnostic tool for the diagnosis, prediction, and monitoring of the effectiveness of therapies for NDs. However, more studies are needed to determine the sensitivity of the proposed candidates. We suggested that the most valuable biomarkers for NDs studies could be groups of metabolites combined with other neuroimaging or molecular techniques. To attain clinically applicable results, the integration of metabolomics with other "omic" techniques might be required.

RevDate: 2023-03-29

Barredo PA, MP Balanay (2023)

Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers.

Membranes, 13(3): pii:membranes13030277.

The study of tau protein aggregation and interactions with other molecules or solvents using molecular dynamics simulations (MDs) is of interest to many researchers to propose new mechanism-based therapeutics for neurodegenerative diseases such as Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy, and other tauopathies. In this review, we present recent MD simulation studies of tau oligomers and fibrils such as tau-NPK, tau-PHF, tau-K18, and tau-R3-R4 monomers and dimers. All-atom simulations by replica exchange MDs and coarse-grained MDs in lipid bilayers and in solution were used. The simulations revealed different mechanisms in the binding of tau in bilayers and in solutions, depending on the peptide size. Phosphorylation is also an important factor in MD simulations. The use of steered MDs was also included to simulate the dissociation of tau fibrils. The exponential improvement in the computing power of computers has led to an increasing number of scientists and engineers using a cost-effective, high-performance computing platform to study how the tau protein interacts and the effects of changing its structure, such as the phosphorylation of tau fibrils.

RevDate: 2023-03-29

Kountouras J, Doulberis M, Papaefthymiou A, et al (2023)

Controlling the Impact of Helicobacter pylori-Related Hyperhomocysteinemia on Neurodegeneration.

Medicina (Kaunas, Lithuania), 59(3): pii:medicina59030504.

Helicobacter pylori infection consists a high global burden affecting more than 50% of the world's population. It is implicated, beyond substantiated local gastric pathologies, i.e., peptic ulcers and gastric cancer, in the pathophysiology of several neurodegenerative disorders, mainly by inducing hyperhomocysteinemia-related brain cortical thinning (BCT). BCT has been advocated as a possible biomarker associated with neurodegenerative central nervous system disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and/or glaucoma, termed as "ocular Alzheimer's disease". According to the infection hypothesis in relation to neurodegeneration, Helicobacter pylori as non-commensal gut microbiome has been advocated as trigger and/or mediator of neurodegenerative diseases, such as the development of Alzheimer's disease. Among others, Helicobacter pylori-related inflammatory mediators, defensins, autophagy, vitamin D, dietary factors, role of probiotics, and some pathogenetic considerations including relevant involved genes are discussed within this opinion article. In conclusion, by controlling the impact of Helicobacter pylori-related hyperhomocysteinemia on neurodegenerative disorders might offer benefits, and additional research is warranted to clarify this crucial topic currently representing a major worldwide burden.

RevDate: 2023-03-29

Contini C, Serrao S, Manconi B, et al (2023)

Characterization of Cystatin B Interactome in Saliva from Healthy Elderly and Alzheimer's Disease Patients.

Life (Basel, Switzerland), 13(3): pii:life13030748.

Cystatin B is a small, multifunctional protein involved in the regulation of inflammation, innate immune response, and neuronal protection and found highly abundant in the brains of patients with Alzheimer's disease (AD). Recently, our study demonstrated a significant association between the level of salivary cystatin B and AD. Since the protein is able to establish protein-protein interaction (PPI) in different contexts and aggregation-prone proteins and the PPI networks are relevant for AD pathogenesis, and due to the relevance of finding new AD markers in peripheral biofluids, we thought it was interesting to study the possible involvement of cystatin B in PPIs in saliva and to evaluate differences and similarities between AD and age-matched elderly healthy controls (HC). For this purpose, we applied a co-immunoprecipitation procedure and a bottom-up proteomics analysis to purify, identify, and quantify cystatin B interactors. Results demonstrated for the first time the existence of a salivary cystatin B-linked multi-protein complex composed by 82 interactors and largely expressed in the body. Interactors are involved in neutrophil activation, antimicrobial activity, modulation of the cytoskeleton and extra-cellular matrix (ECM), and glucose metabolism. Preliminary quantitative data showed significantly lower levels of triosophosphate isomerase 1 and higher levels of mucin 7, BPI, and matrix Gla protein in AD with respect to HC, suggesting implications associated with AD of altered glucose metabolism, antibacterial activities, and calcification-associated processes. Data are available via ProteomeXchange with identifiers PXD039286 and PXD030679.

RevDate: 2023-03-29

Karagecili H, İzol E, Kirecci E, et al (2023)

Determination of Antioxidant, Anti-Alzheimer, Antidiabetic, Antiglaucoma and Antimicrobial Effects of Zivzik Pomegranate (Punica granatum)-A Chemical Profiling by LC-MS/MS.

Life (Basel, Switzerland), 13(3): pii:life13030735.

Zivzik pomegranate (Punica granatum) has recently sparked considerable interest due to its nutritional and antioxidant properties. To evaluate the antioxidant capacities of P. granatum juice, ethanol (EEZP), and water (WEZP) extracts from peel and seed, the antioxidant methods of 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid radical (ABTS[•+]) scavenging, 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH[•]) scavenging, Fe[3+]-2,4,6-tris(2-pyridyl)-S-triazine (TPTZ) reducing, Fe[3+] reducing, and Cu[2+] reducing methods were used. The antioxidant capacities of samples were compared with the most commonly used synthetic antioxidants, i.e., BHA, BHT, α-tocopherol, and Trolox. In terms of setting an example, the IC50 values of EEZP for ABTS[•+] and DPPH[•] scavenging activities were found to be lower than standards, at 5.9 and 16.1 μg/mL, respectively. The phenolic and flavonoid contents in EEZP peel were 59.7 mg GAE/g and 88.0 mg QE/g, respectively. Inhibition of α-glycosidase, α-amylase, acetylcholinesterase, and human carbonic anhydrase II (hCA II) enzymes was also investigated. EEZP demonstrated IC50 values of 7.3 μg/mL against α-glycosidase, 317.7 μg/mL against α-amylase, 19.7 μg/mL against acetylcholinesterase (AChE), and 106.3 μg/mL against CA II enzymes. A total of 53 phenolic compounds were scanned, and 30 compounds were determined using LC-MS/MS. E. coli and S. aureus bacteria were resistant to all four antibiotics used as standards in hospitals.

RevDate: 2023-03-29

Hussain A, Sheikh Z, M Subramanian (2023)

The Eye as a Diagnostic Tool for Alzheimer's Disease.

Life (Basel, Switzerland), 13(3): pii:life13030726.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder impacting cognition, function, and behavior in the elderly population. While there are currently no disease-modifying agents capable of curing AD, early diagnosis and management in the preclinical stage can significantly improve patient morbidity and life expectancy. Currently, the diagnosis of Alzheimer's disease is a clinical one, often supplemented by invasive and expensive biomarker testing. Over the last decade, significant advancements have been made in our understanding of AD and the role of ocular tissue as a potential biomarker. Ocular biomarkers hold the potential to provide noninvasive and easily accessible diagnostic and monitoring capabilities. This review summarizes current research for detecting biomarkers of Alzheimer's disease in ocular tissue.

RevDate: 2023-03-29

Numakawa T, R Kajihara (2023)

Neurotrophins and Other Growth Factors in the Pathogenesis of Alzheimer's Disease.

Life (Basel, Switzerland), 13(3): pii:life13030647.

The involvement of the changed expression/function of neurotrophic factors in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), has been suggested. AD is one of the age-related dementias, and is characterized by cognitive impairment with decreased memory function. Developing evidence demonstrates that decreased cell survival, synaptic dysfunction, and reduced neurogenesis are involved in the pathogenesis of AD. On the other hand, it is well known that neurotrophic factors, especially brain-derived neurotrophic factor (BDNF) and its high-affinity receptor TrkB, have multiple roles in the central nervous system (CNS), including neuronal maintenance, synaptic plasticity, and neurogenesis, which are closely linked to learning and memory function. Thus, many investigations regarding therapeutic approaches to AD, and/or the screening of novel drug candidates for its treatment, focus on upregulation of the BDNF/TrkB system. Furthermore, current studies also demonstrate that GDNF, IGF1, and bFGF, which play roles in neuroprotection, are associated with AD. In this review, we introduce data demonstrating close relationships between the pathogenesis of AD, neurotrophic factors, and drug candidates, including natural compounds that upregulate the BDNF-mediated neurotrophic system.

RevDate: 2023-03-29

Kesidou E, Theotokis P, Damianidou O, et al (2023)

CNS Ageing in Health and Neurodegenerative Disorders.

Journal of clinical medicine, 12(6): pii:jcm12062255.

The process of ageing is characteristic of multicellular organisms associated with late stages of the lifecycle and is manifested through a plethora of phenotypes. Its underlying mechanisms are correlated with age-dependent diseases, especially neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS) that are accompanied by social and financial difficulties for patients. Over time, people not only become more prone to neurodegeneration but they also lose the ability to trigger pivotal restorative mechanisms. In this review, we attempt to present the already known molecular and cellular hallmarks that characterize ageing in association with their impact on the central nervous system (CNS)'s structure and function intensifying possible preexisting pathogenetic conditions. A thorough and elucidative study of the underlying mechanisms of ageing will be able to contribute further to the development of new therapeutic interventions to effectively treat age-dependent manifestations of neurodegenerative diseases.

RevDate: 2023-03-29

Lien WC, Yeh CH, Chang CY, et al (2023)

Convolutional Neural Networks to Classify Alzheimer's Disease Severity Based on SPECT Images: A Comparative Study.

Journal of clinical medicine, 12(6): pii:jcm12062218.

Image recognition and neuroimaging are increasingly being used to understand the progression of Alzheimer's disease (AD). However, image data from single-photon emission computed tomography (SPECT) are limited. Medical image analysis requires large, labeled training datasets. Therefore, studies have focused on overcoming this problem. In this study, the detection performance of five convolutional neural network (CNN) models (MobileNet V2 and NASNetMobile (lightweight models); VGG16, Inception V3, and ResNet (heavier weight models)) on medical images was compared to establish a classification model for epidemiological research. Brain scan image data were collected from 99 subjects, and 4711 images were used. Demographic data were compared using the chi-squared test and one-way analysis of variance with Bonferroni's post hoc test. Accuracy and loss functions were used to evaluate the performance of CNN models. The cognitive abilities screening instrument and mini mental state exam scores of subjects with a clinical dementia rating (CDR) of 2 were considerably lower than those of subjects with a CDR of 1 or 0.5. This study analyzed the classification performance of various CNN models for medical images and proved the effectiveness of transfer learning in identifying the mild cognitive impairment, mild AD, and moderate AD scoring based on SPECT images.

RevDate: 2023-03-29

Sakalauskas A, Ziaunys M, Snieckute R, et al (2023)

The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation.

International journal of molecular sciences, 24(6): pii:ijms24065991.

The main pathological hallmark of Alzheimer's disease (AD) is the aggregation of amyloid-β into amyloid fibrils, leading to a neurodegeneration cascade. The current medications are far from sufficient to prevent the onset of the disease, hence requiring more research to find new alternative drugs for curing AD. In vitro inhibition experiments are one of the primary tools in testing whether a molecule may be potent to impede the aggregation of amyloid-beta peptide (Aβ42). However, kinetic experiments in vitro do not match the mechanism found when aggregating Aβ42 in cerebrospinal fluid. The different aggregation mechanisms and the composition of the reaction mixtures may also impact the characteristics of the inhibitor molecules. For this reason, altering the reaction mixture to resemble components found in cerebrospinal fluid (CSF) is critical to partially compensate for the mismatch between the inhibition experiments in vivo and in vitro. In this study, we used an artificial cerebrospinal fluid that contained the major components found in CSF and performed Aβ42 aggregation inhibition studies using oxidized epigallocatechin-3-gallate (EGCG) and fluorinated benzenesulfonamide VR16-09. This led to a discovery of a complete turnaround of their inhibitory characteristics, rendering EGCG ineffective while significantly improving the efficacy of VR16-09. HSA was the main contributor in the mixture that significantly increased the anti-amyloid characteristics of VR16-09.

RevDate: 2023-03-29

Dib S, Loiola RA, Sevin E, et al (2023)

TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1.

International journal of molecular sciences, 24(6): pii:ijms24065992.

Neuroinflammation and brain lipid imbalances are observed in Alzheimer's disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes (HBP) of the neurovascular unit. In cultivated HBP, TNFα activates the LXR pathway and increases the expression of one of its target genes, the transporter ATP-binding cassette family A member 1 (ABCA1), while ABCG1 is not expressed. Apolipoprotein E (APOE) synthesis and release are diminished. The cholesterol efflux is promoted, but is not inhibited, when ABCA1 or LXR are blocked. Moreover, as for TNFα, direct LXR activation by the agonist (T0901317) increases ABCA1 expression and the associated cholesterol efflux. However, this process is abolished when LXR/ABCA1 are both inhibited. Neither the other ABC transporters nor the SR-BI are involved in this TNFα-mediated lipid efflux regulation. We also report that inflammation increases ABCB1 expression and function. In conclusion, our data suggest that inflammation increases HBP protection against xenobiotics and triggers an LXR/ABCA1 independent cholesterol release. Understanding the molecular mechanisms regulating this efflux at the level of the neurovascular unit remains fundamental to the characterization of links between neuroinflammation, cholesterol and HBP function in neurodegenerative disorders.

RevDate: 2023-03-29

Poppell M, Hammel G, Y Ren (2023)

Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases.

International journal of molecular sciences, 24(6): pii:ijms24065925.

Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune disorders. How these cells may be contributing to the adaptive immune response and potentially perpetuating the progression of neurodegenerative diseases and neural injuries is not fully understood. Within this review, we hope to illustrate the role that macrophages and microglia play as initiators of adaptive immune response in various CNS diseases by offering evidence of: (1) the types of immune responses and the processes of antigen presentation in each disease, (2) receptors involved in macrophage/microglial phagocytosis of disease-related cell debris or molecules, and, finally, (3) the implications of macrophages/microglia on the pathogenesis of the diseases.

RevDate: 2023-03-29

Decandia D, Gelfo F, Landolfo E, et al (2023)

Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer's Disease Animal Models of Lipopolysaccharide-Induced Inflammation.

International journal of molecular sciences, 24(6): pii:ijms24065921.

Alzheimer's disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation.

RevDate: 2023-03-29

Santiago JA, Quinn JP, JA Potashkin (2023)

Co-Expression Network Analysis Identifies Molecular Determinants of Loneliness Associated with Neuropsychiatric and Neurodegenerative Diseases.

International journal of molecular sciences, 24(6): pii:ijms24065909.

Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular 'switches' responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-β, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer's (AD) and Parkinson's diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, BCAM, NECTIN2, NPAS3, RBM38, PELI1, DPP10, and ASGR2, have been identified as genetic risk factors for AD. Likewise, switch genes HLA-DRB5, ALDOA, and GPNMB are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, HLA-DRB5, ARHGAP15, COL4A1, RBM38, DMD, LGALS3BP, WSCD2, CYTH4, and CNTRL, overlapped with known genetic variants in depression. Seven switch genes, NPAS3, ARHGAP15, LGALS3BP, DPP10, SMYD3, CPXCR1, and HLA-DRB5 were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals.

RevDate: 2023-03-29

Wang C, Zou Q, Pu Y, et al (2023)

Berberine Rescues D-Ribose-Induced Alzheimer's Pathology via Promoting Mitophagy.

International journal of molecular sciences, 24(6): pii:ijms24065896.

Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer's pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation. APP/PS1 mice and N2a cells were treated with D-ribose, BBR, and mitophagy inhibitor Mdivi-1 to observe their effects on mitochondrial morphology, mitophagy, neuron histology, AD pathology, animal behavior, and PINK1 methylation. The results showed that D-ribose induced mitochondrial dysfunction, mitophagy damage, and cognitive impairment. However, BBR inhibition of PINK1 promoter methylation can reverse the above effects caused by D-ribose, improve mitochondrial function, and restore mitophagy through the PINK1-Parkin pathway, thus reducing cognitive deficits and the burden of AD pathology. This experiment puts a new light on the mechanism of action of D-ribose in cognitive impairment and reveals new insights in the use of BBR for AD treatment.

RevDate: 2023-03-29

Loh D, RJ Reiter (2023)

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia.

International journal of molecular sciences, 24(6): pii:ijms24065835.

The swift rise in acceptance of molecular principles defining phase separation by a broad array of scientific disciplines is shadowed by increasing discoveries linking phase separation to pathological aggregations associated with numerous neurodegenerative disorders, including Alzheimer's disease, that contribute to dementia. Phase separation is powered by multivalent macromolecular interactions. Importantly, the release of water molecules from protein hydration shells into bulk creates entropic gains that promote phase separation and the subsequent generation of insoluble cytotoxic aggregates that drive healthy brain cells into diseased states. Higher viscosity in interfacial waters and limited hydration in interiors of biomolecular condensates facilitate phase separation. Light, water, and melatonin constitute an ancient synergy that ensures adequate protein hydration to prevent aberrant phase separation. The 670 nm visible red wavelength found in sunlight and employed in photobiomodulation reduces interfacial and mitochondrial matrix viscosity to enhance ATP production via increasing ATP synthase motor efficiency. Melatonin is a potent antioxidant that lowers viscosity to increase ATP by scavenging excess reactive oxygen species and free radicals. Reduced viscosity by light and melatonin elevates the availability of free water molecules that allow melatonin to adopt favorable conformations that enhance intrinsic features, including binding interactions with adenosine that reinforces the adenosine moiety effect of ATP responsible for preventing water removal that causes hydrophobic collapse and aggregation in phase separation. Precise recalibration of interspecies melatonin dosages that account for differences in metabolic rates and bioavailability will ensure the efficacious reinstatement of the once-powerful ancient synergy between light, water, and melatonin in a modern world.

RevDate: 2023-03-29

Martínez-Iglesias O, Naidoo V, Carril JC, et al (2023)

Gene Expression Profiling as a Novel Diagnostic Tool for Neurodegenerative Disorders.

International journal of molecular sciences, 24(6): pii:ijms24065746.

There is a lack of effective diagnostic biomarkers for neurodegenerative disorders (NDDs). Here, we established gene expression profiles for diagnosing Alzheimer's disease (AD), Parkinson's disease (PD), and vascular (VaD)/mixed dementia. Patients with AD had decreased APOE, PSEN1, and ABCA7 mRNA expression. Subjects with VaD/mixed dementia had 98% higher PICALM mRNA levels, but 75% lower ABCA7 mRNA expression than healthy individuals. Patients with PD and PD-related disorders showed increased SNCA mRNA levels. There were no differences in mRNA expression for OPRK1, NTRK2, and LRRK2 between healthy subjects and NDD patients. APOE mRNA expression had high diagnostic accuracy for AD, and moderate accuracy for PD and VaD/mixed dementia. PSEN1 mRNA expression showed promising accuracy for AD. PICALM mRNA expression was less accurate as a biomarker for AD. ABCA7 and SNCA mRNA expression showed high-to-excellent diagnostic accuracy for AD and PD, and moderate-to-high accuracy for VaD/mixed dementia. The APOE E4 allele reduced APOE expression in patients with different APOE genotypes. There was no association between PSEN1, PICALM, ABCA7, and SNCA gene polymorphisms and expression. Our study suggests that gene expression analysis has diagnostic value for NDDs and provides a liquid biopsy alternative to current diagnostic methods.

RevDate: 2023-03-29

Kosenko E, Tikhonova L, Alilova G, et al (2023)

Erythrocytes Functionality in SARS-CoV-2 Infection: Potential Link with Alzheimer's Disease.

International journal of molecular sciences, 24(6): pii:ijms24065739.

Coronavirus disease 2019 (COVID-19) is a rapidly spreading acute respiratory infection caused by SARS-CoV-2. The pathogenesis of the disease remains unclear. Recently, several hypotheses have emerged to explain the mechanism of interaction between SARS-CoV-2 and erythrocytes, and its negative effect on the oxygen-transport function that depends on erythrocyte metabolism, which is responsible for hemoglobin-oxygen affinity (Hb-O2 affinity). In clinical settings, the modulators of the Hb-O2 affinity are not currently measured to assess tissue oxygenation, thereby providing inadequate evaluation of erythrocyte dysfunction in the integrated oxygen-transport system. To discover more about hypoxemia/hypoxia in COVID-19 patients, this review highlights the need for further investigation of the relationship between biochemical aberrations in erythrocytes and oxygen-transport efficiency. Furthermore, patients with severe COVID-19 experience symptoms similar to Alzheimer's, suggesting that their brains have been altered in ways that increase the likelihood of Alzheimer's. Mindful of the partly assessed role of structural, metabolic abnormalities that underlie erythrocyte dysfunction in the pathophysiology of Alzheimer's disease (AD), we further summarize the available data showing that COVID-19 neurocognitive impairments most probably share similar patterns with known mechanisms of brain dysfunctions in AD. Identification of parameters responsible for erythrocyte function that vary under SARS-CoV-2 may contribute to the search for additional components of progressive and irreversible failure in the integrated oxygen-transport system leading to tissue hypoperfusion. This is particularly relevant for the older generation who experience age-related disorders of erythrocyte metabolism and are prone to AD, and provide an opportunity for new personalized therapies to control this deadly infection.

RevDate: 2023-03-29

Tun X, Wang EJ, Gao Z, et al (2023)

Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer's Disease.

International journal of molecular sciences, 24(6): pii:ijms24065697.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes that ultimately lead to dementia. Currently, 50 million people worldwide suffer from dementia related to AD, and the pathogenesis underlying AD pathology and cognitive decline is unknown. While AD is primarily a neurological disease of the brain, individuals with AD often experience intestinal disorders, and gut abnormalities have been implicated as a major risk factor in the development of AD and relevant dementia. However, the mechanisms that mediate gut injury and contribute to the vicious cycle between gut abnormalities and brain injury in AD remain unknown. In the present study, a bioinformatics analysis was performed on the proteomics data of variously aged AD mouse colon tissues. We found that levels of integrin β3 and β-galactosidase (β-gal), two markers of cellular senescence, increased with age in the colonic tissue of mice with AD. The advanced artificial intelligence (AI)-based prediction of AD risk also demonstrated the association between integrin β3 and β-gal and AD phenotypes. Moreover, we showed that elevated integrin β3 levels were accompanied by senescence phenotypes and immune cell accumulation in AD mouse colonic tissue. Further, integrin β3 genetic downregulation abolished upregulated senescence markers and inflammatory responses in colonic epithelial cells in conditions associated with AD. We provide a new understanding of the molecular actions underpinning inflammatory responses during AD and suggest integrin β3 may function as novel target mediating gut abnormalities in this disease.

RevDate: 2023-03-29

Dong L, Shen Y, Li H, et al (2023)

Shared Genes of PPARG and NOS2 in Alzheimer's Disease and Ulcerative Colitis Drive Macrophages and Microglia Polarization: Evidence from Bioinformatics Analysis and Following Validation.

International journal of molecular sciences, 24(6): pii:ijms24065651.

Emerging evidence shows that peripheral systemic inflammation, such as inflammatory bowel disease (IBD), has a close even interaction with central nervous disorders such as Alzheimer's disease (AD). This study is designed to further clarify the relationship between AD and ulcerative colitis (UC, a subclass of IBD). The GEO database was used to download gene expression profiles for AD (GSE5281) and UC (GSE47908). Bioinformatics analysis included GSEA, KEGG pathway, Gene Ontology (GO), WikiPathways, PPI network, and hub gene identification. After screening the shared genes, qRT-PCR, Western blot, and immunofluorescence were used to verify the reliability of the dataset and further confirm the shared genes. GSEA, KEGG, GO, and WikiPathways suggested that PPARG and NOS2 were identified as shared genes and hub genes by cytoHubba in AD and UC and further validated via qRT-PCR and Western blot. Our work identified PPARG and NOS2 are shared genes of AD and UC. They drive macrophages and microglia heterogeneous polarization, which may be potential targets for treating neural dysfunction induced by systemic inflammation and vice versa.

RevDate: 2023-03-29

Barr JL, Feehan M, Tak C, et al (2023)

Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence.

International journal of molecular sciences, 24(6): pii:ijms24065636.

Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41-71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients' glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System's pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10[-3]) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10[-3]) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer's disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62-5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10[-6]) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11-0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47-58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.

RevDate: 2023-03-29

Li H, Huynh TN, Duong MT, et al (2023)

ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-like Receptor 4 in Microglia.

International journal of molecular sciences, 24(6): pii:ijms24065616.

Cholesterol is stored as cholesteryl esters by the enzymes acyl-CoA:cholesterol acyltransferases/sterol O:acyltransferases (ACATs/SOATs). ACAT1 blockade (A1B) ameliorates the pro-inflammatory responses of macrophages to lipopolysaccharides (LPS) and cholesterol loading. However, the mediators involved in transmitting the effects of A1B in immune cells is unknown. Microglial Acat1/Soat1 expression is elevated in many neurodegenerative diseases and in acute neuroinflammation. We evaluated LPS-induced neuroinflammation experiments in control vs. myeloid-specific Acat1/Soat1 knockout mice. We also evaluated LPS-induced neuroinflammation in microglial N9 cells with and without pre-treatment with K-604, a selective ACAT1 inhibitor. Biochemical and microscopy assays were used to monitor the fate of Toll-Like Receptor 4 (TLR4), the receptor at the plasma membrane and the endosomal membrane that mediates pro-inflammatory signaling cascades. In the hippocampus and cortex, results revealed that Acat1/Soat1 inactivation in myeloid cell lineage markedly attenuated LPS-induced activation of pro-inflammatory response genes. Studies in microglial N9 cells showed that pre-incubation with K-604 significantly reduced the LPS-induced pro-inflammatory responses. Further studies showed that K-604 decreased the total TLR4 protein content by increasing TLR4 endocytosis, thus enhancing the trafficking of TLR4 to the lysosomes for degradation. We concluded that A1B alters the intracellular fate of TLR4 and suppresses its pro-inflammatory signaling cascade in response to LPS.

RevDate: 2023-03-29

Gulino R, Nunziata D, de Leo G, et al (2023)

Hippocampal Noradrenaline Is a Positive Regulator of Spatial Working Memory and Neurogenesis in the Rat.

International journal of molecular sciences, 24(6): pii:ijms24065613.

Loss of noradrenaline (NA)-rich afferents from the Locus Coeruleus (LC) ascending to the hippocampal formation has been reported to dramatically affect distinct aspects of cognitive function, in addition to reducing the proliferation of neural progenitors in the dentate gyrus. Here, the hypothesis that reinstating hippocampal noradrenergic neurotransmission with transplanted LC-derived neuroblasts would concurrently normalize both cognitive performance and adult hippocampal neurogenesis was investigated. Post-natal day (PD) 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents followed, 4 days later, by the bilateral intrahippocampal implantation of LC noradrenergic-rich or control cerebellar (CBL) neuroblasts. Starting from 4 weeks and up to about 9 months post-surgery, sensory-motor and spatial navigation abilities were evaluated, followed by post-mortem semiquantitative tissue analyses. All animals in the Control, Lesion, Noradrenergic Transplant and Control CBL Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task. By contrast, working memory abilities were seen to be consistently impaired in the Lesion-only and Control CBL-Transplanted rats, which also exhibited a virtually complete noradrenergic fiber depletion and a significant 62-65% reduction in proliferating 5-bromo-2'deoxyuridine (BrdU)-positive progenitors in the dentate gyrus. Notably, the noradrenergic reinnervation promoted by the grafted LC, but not cerebellar neuroblasts, significantly ameliorated working memory performance and reinstated a fairly normal density of proliferating progenitors. Thus, LC-derived noradrenergic inputs may act as positive regulators of hippocampus-dependent spatial working memory possibly via the concurrent maintenance of normal progenitor proliferation in the dentate gyrus.

RevDate: 2023-03-29

Fei Z, Pei R, Pan B, et al (2023)

Antibody Assay and Anti-Inflammatory Function Evaluation of Therapeutic Potential of Different Intravenous Immunoglobulins for Alzheimer's Disease.

International journal of molecular sciences, 24(6): pii:ijms24065549.

Alzheimer's disease (AD) is a common neurodegenerative disease that currently has no known cure. Intravenous immunoglobulin (IVIG), which contains AD-related antibodies and has anti-inflammatory properties, has shown potential as a treatment for AD. However, the efficacy of clinical trials involving AD patients treated with IVIG has been inconsistent. Our previous study found that different IVIGs had significantly varied therapeutic effects on 3xTg-AD mice. In order to investigate the relationship between the composition and function of IVIG and its efficacy in treating AD, we selected three IVIGs that showed notable differences in therapeutic effects. Then, the concentrations of specific antibodies against β-amyloid (Aβ)42, tau, and hyperphosphorylated tau (p-tau) in three IVIGs, as well as their effects on systemic inflammation induced by lipopolysaccharide (LPS) in Balb/c mice, were analyzed and compared in this study. The results indicated that these IVIGs differed greatly in anti-Aβ42/tau antibody concentration and anti-p-tau ratio, and improved LPS-stimulated peripheral inflammation, liver and kidney injury, and neuroinflammation in Balb/c mice to varying degrees. Combined with our previous results, the efficacy of IVIG against AD may be positively correlated with its level of AD-related antibodies and anti-inflammatory ability. AD-related antibody analysis and functional evaluation of IVIG should be given sufficient attention before clinical trials, as this may greatly affect the therapeutic effect of AD treatment.

RevDate: 2023-03-29

Höhn L, Hußler W, Richter A, et al (2023)

Extracellular Matrix Changes in Subcellular Brain Fractions and Cerebrospinal Fluid of Alzheimer's Disease Patients.

International journal of molecular sciences, 24(6): pii:ijms24065532.

The brain's extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer's disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aβ1-40. Negative correlations were detected with the Aβ ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process.

RevDate: 2023-03-29

Harned TC, Stan RV, Cao Z, et al (2023)

Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity.

International journal of molecular sciences, 24(6): pii:ijms24065525.

Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). The genetic and pharmacological blockade of acyl-CoA:cholesterol acyltransferase 1/sterol O-acyltransferase 1 (ACAT1/SOAT1), a cholesterol storage enzyme found on the endoplasmic reticulum (ER) and enriched at the mitochondria-associated ER membrane (MAM), has been shown to reduce amyloid pathology and rescue cognitive deficits in mouse models of AD. Additionally, blocking ACAT1/SOAT1 activity stimulates autophagy and lysosomal biogenesis; however, the exact molecular connection between the ACAT1/SOAT1 blockade and these observed benefits remain unknown. Here, using biochemical fractionation techniques, we observe cholesterol accumulation at the MAM which leads to ACAT1/SOAT1 enrichment in this domain. MAM proteomics data suggests that ACAT1/SOAT1 inhibition strengthens the ER-mitochondria connection. Confocal and electron microscopy confirms that ACAT1/SOAT1 inhibition increases the number of ER-mitochondria contact sites and strengthens this connection by shortening the distance between these two organelles. This work demonstrates how directly manipulating local cholesterol levels at the MAM can alter inter-organellar contact sites and suggests that cholesterol buildup at the MAM is the impetus behind the therapeutic benefits of ACAT1/SOAT1 inhibition.

RevDate: 2023-03-29

Hamarsha A, Balachandran K, Sailan AT, et al (2023)

Predicting Key Genes and Therapeutic Molecular Modelling to Explain the Association between Porphyromonas gingivalis (P. gingivalis) and Alzheimer's Disease (AD).

International journal of molecular sciences, 24(6): pii:ijms24065432.

The association between Porphyromonas gingivalis (P. gingivalis) and Alzheimer's disease (AD) remains unclear. The major aim of this study was to elucidate the role of genes and molecular targets in P. gingivalis-associated AD. Two Gene Expression Omnibus (GEO) datasets, GSE5281 for AD (n = 84 Alzheimer's, n = 74 control) and GSE9723 (n = 4 P. gingivalis, n = 4 control), were downloaded from the GEO database. Differentially expressed genes (DEGs) were obtained, and genes common to both diseases were drawn. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis was performed from the top 100 genes (50 upregulated and 50 downregulated genes). We then proceeded with CMap analysis to screen for possible small drug molecules targeting these genes. Subsequently, we performed molecular dynamics simulations. A total of 10 common genes (CALD1, HES1, ID3, PLK2, PPP2R2D, RASGRF1, SUN1, VPS33B, WTH3DI/RAB6A, and ZFP36L1) were identified with a p-value < 0.05. The PPI network of the top 100 genes showed UCHL1, SST, CHGB, CALY, and INA to be common in the MCC, DMNC, and MNC domains. Out of the 10 common genes identified, only 1 was mapped in CMap. We found three candidate small drug molecules to be a fit for PLK2, namely PubChem ID: 24971422, 11364421, and 49792852. We then performed molecular docking of PLK2 with PubChem ID: 24971422, 11364421, and 49792852. The best target, 11364421, was used to conduct the molecular dynamics simulations. The results of this study unravel novel genes to P. gingivalis-associated AD that warrant further validation.

RevDate: 2023-03-29

Stańczykiewicz B, Goszczyński TM, Migdał P, et al (2023)

Effect of Ovocystatin on Amyloid β 1-42 Aggregation-In Vitro Studies.

International journal of molecular sciences, 24(6): pii:ijms24065433.

Amyloid β peptides (Aβ) aggregating in the brain have a potential neurotoxic effect and are believed to be a major cause of Alzheimer's disease (AD) development. Thus, inhibiting amyloid polypeptide aggregation seems to be a promising approach to the therapy and prevention of this neurodegenerative disease. The research presented here is directed at the determination of the inhibitory activity of ovocystatin, the cysteine protease inhibitor isolated from egg white, on Aβ42 fibril genesis in vitro. Thioflavin-T (ThT) assays, which determine the degree of aggregation of amyloid peptides based on fluorescence measurement, circular dichroism spectroscopy (CD), and transmission electron microscopy (TEM) have been used to assess the inhibition of amyloid fibril formation by ovocystatin. Amyloid beta 42 oligomer toxicity was measured using the MTT test. The results have shown that ovocystatin possesses Aβ42 anti-aggregation activity and inhibits Aβ42 oligomer toxicity in PC12 cells. The results of this work may help in the development of potential substances able to prevent or delay the process of beta-amyloid aggregation-one of the main reasons for Alzheimer's disease.

RevDate: 2023-03-29

Penke B, Szűcs M, F Bogár (2023)

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer's Disease.

International journal of molecular sciences, 24(6): pii:ijms24065383.

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60-80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: β-amyloid (Aβ) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aβ and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aβ and pTau aggregates has been an old drug target. Recently, successful Aβ clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research.

RevDate: 2023-03-29

Fairley LH, Lejri I, Grimm A, et al (2023)

Spermidine Rescues Bioenergetic and Mitophagy Deficits Induced by Disease-Associated Tau Protein.

International journal of molecular sciences, 24(6): pii:ijms24065297.

Abnormal tau build-up is a hallmark of Alzheimer's disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal tau impairs almost every aspect of mitochondrial function, from mitochondrial respiration to mitophagy. The aim of our study was to investigate the effects of spermidine, a polyamine which exerts neuroprotective effects, on mitochondrial function in a cellular model of tauopathy. Recent evidence identified autophagy as the main mechanism of action of spermidine on life-span prolongation and neuroprotection, but the effects of spermidine on abnormal tau-induced mitochondrial dysfunction have not yet been investigated. We used SH-SY5Y cells stably expressing a mutant form of human tau protein (P301L tau mutation) or cells expressing the empty vector (control cells). We showed that spermidine improved mitochondrial respiration, mitochondrial membrane potential as well as adenosine triphosphate (ATP) production in both control and P301L tau-expressing cells. We also showed that spermidine decreased the level of free radicals, increased autophagy and restored P301L tau-induced impairments in mitophagy. Overall, our findings suggest that spermidine supplementation might represent an attractive therapeutic approach to prevent/counteract tau-related mitochondrial impairments.

RevDate: 2023-03-29

Tautou M, Descamps F, Larchanché PE, et al (2023)

A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP[Swe]/PSEN1[ΔE9] Mice Model of Amyloid Pathology.

International journal of molecular sciences, 24(6): pii:ijms24065285.

The progress in Alzheimer's disease (AD) treatment suggests a combined therapeutic approach targeting the two lesional processes of AD, which include amyloid plaques made of toxic Aβ species and neurofibrillary tangles formed of aggregates of abnormally modified Tau proteins. A pharmacophoric design, novel drug synthesis, and structure-activity relationship enabled the selection of a polyamino biaryl PEL24-199 compound. The pharmacologic activity consists of a non-competitive β-secretase (BACE1) modulatory activity in cells. Curative treatment of the Thy-Tau22 model of Tau pathology restores short-term spatial memory, decreases neurofibrillary degeneration, and alleviates astrogliosis and neuroinflammatory reactions. Modulatory effects of PEL24-199 towards APP catalytic byproducts are described in vitro, but whether PEL24-199 can alleviate the Aβ plaque load and associated inflammatory counterparts in vivo remains to be elucidated. We investigated short- and long-term spatial memory, Aβ plaque load, and inflammatory processes in APP[Swe]/PSEN1[ΔE9] PEL24-199 treated transgenic model of amyloid pathology to achieve this objective. PEL24-199 curative treatment induced the recovery of spatial memory and decreased the amyloid plaque load in association with decreased astrogliosis and neuroinflammation. The present results underline the synthesis and selection of a promising polyaminobiaryl-based drug that modulates both Tau and, in this case, APP pathology in vivo via a neuroinflammatory-dependent process.

RevDate: 2023-03-29

Park JS, Choe K, Khan A, et al (2023)

Establishing Co-Culture Blood-Brain Barrier Models for Different Neurodegeneration Conditions to Understand Its Effect on BBB Integrity.

International journal of molecular sciences, 24(6): pii:ijms24065283.

The blood-brain barrier (BBB) is a functional interface that provides selective permeability, protection from toxic substances, transport of nutrients, and clearance of brain metabolites. Additionally, BBB disruption has been shown to play a role in many neurodegenerative conditions and diseases. Therefore, the aim of this study was to establish a functional, convenient, and efficient in vitro co-cultured BBB model that can be used for several physiological conditions related to BBB disruption. Mouse brain-derived endothelial (bEnd.3) and astrocyte (C8-D1A) cells were co-cultured on transwell membranes to establish an intact and functional in vitro model. The co-cultured model and its effects on different neurological diseases and stress conditions, including Alzheimer's disease (AD), neuroinflammation, and obesity, have been examined by transendothelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran, and tight junction protein analyses. Scanning electron microscope images showed evidence of astrocyte end-feet processes passing through the membrane of the transwell. Moreover, the co-cultured model showed effective barrier properties in the TEER, FITC, and solvent persistence and leakage tests when compared to the mono-cultured model. Additionally, the immunoblot results showed that the expression of tight junction proteins such as zonula occludens-1 (ZO-1), claudin-5, and occludin-1 was enhanced in the co-culture. Lastly, under disease conditions, the BBB structural and functional integrity was decreased. The present study demonstrated that the co-cultured in vitro model mimicked the BBB's structural and functional integrity and, under disease conditions, the co-cultured model showed similar BBB damages. Therefore, the present in vitro BBB model can be used as a convenient and efficient experimental tool to investigate a wide range of BBB-related pathological and physiological studies.

RevDate: 2023-03-29

Zhou W, Lei B, Yang C, et al (2023)

Artemisia annua Extract Improves the Cognitive Deficits and Reverses the Pathological Changes of Alzheimer's Disease via Regulating YAP Signaling.

International journal of molecular sciences, 24(6): pii:ijms24065259.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the occurrence of cognitive deficits. With no effective treatments available, the search for new effective therapies has become a major focus of interest. In the present study, we describe the potential therapeutic effect of Artemisia annua (A. annua) extract on AD. Nine-month-old female 3xTg AD mice were treated with A. annua extract for three months via oral administration. Animals assigned to WT and model groups were administrated with an equal volume of water for the same period. Treated AD mice significantly improved the cognitive deficits and exhibited reduced Aβ accumulation, hyper-phosphorylation of tau, inflammatory factor release and apoptosis when compared with untreated AD mice. Moreover, A. annua extract promoted the survival and proliferation of neural progenitor cells (NPS) and increased the expression of synaptic proteins. Further assessment of the implicated mechanisms revealed that A. annua extract regulates the YAP signaling pathway in 3xTg AD mice. Further studies comprised the incubation of PC12 cells with Aβ1-42 at a concentration of 8 μM with or without different concentrations of A. annua extract for 24 h. Obtained ROS levels, mitochondrial membrane potential, caspase-3 activity, neuronal cell apoptosis and assessment of the signaling pathways involved was performed using western blot and immunofluorescence staining. The obtained results showed that A. annua extract significantly reversed the Aβ1-42-induced increase in ROS levels, caspase-3 activity and neuronal cell apoptosis in vitro. Moreover, either inhibition of the YAP signaling pathway, using a specific inhibitor or CRISPR cas9 knockout of YAP gene, reduced the neuroprotective effect of the A. annua extract. These findings suggest that A. annua extract may be a new multi-target anti-AD drug with potential use in the prevention and treatment of AD.

RevDate: 2023-03-29

Panizzutti B, Skvarc D, Lin S, et al (2023)

Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis.

International journal of molecular sciences, 24(6): pii:ijms24065250.

Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.

RevDate: 2023-03-29

Balmorez T, Sakazaki A, S Murakami (2023)

Genetic Networks of Alzheimer's Disease, Aging, and Longevity in Humans.

International journal of molecular sciences, 24(6): pii:ijms24065178.

Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer's disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value < 1.00 × 10[-5] using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p < 1.00 × 10[-5], of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression (p = 4.05 × 10[-11]) including ApoE, SOD2, TP53, and TGFB1 (p = 2.84 × 10[-10]); protein metabolism and SUMOylation, including E3 ligases and target proteins (p = 1.08 × 10[-7]); ERBB4 signal transduction (p = 2.69 × 10[-6]); the immune system, including IL-3 and IL-13 (p = 3.83 × 10[-6]); programmed cell death (p = 4.36 × 10[-6]); and platelet degranulation (p = 8.16 × 10[-6]), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 (p = 7.64 × 10[-8]), plasma lipoprotein assembly, remodeling and clearance (p < 4.02 × 10[-6]), and the metabolism of fat-soluble vitamins (p = 1.96 × 10[-5]). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging.

RevDate: 2023-03-29

Banerjee S, Baghel D, Pacheco de Oliveira A, et al (2023)

β-Carotene, a Potent Amyloid Aggregation Inhibitor, Promotes Disordered Aβ Fibrillar Structure.

International journal of molecular sciences, 24(6): pii:ijms24065175.

The aggregation of amyloid beta (Aβ) into fibrillar aggregates is a key feature of Alzheimer's disease (AD) pathology. β-carotene and related compounds have been shown to associate with amyloid aggregates and have direct impact on the formation of amyloid fibrils. However, the precise effect of β-carotene on the structure of amyloid aggregates is not known, which poses a limitation towards developing it as a potential AD therapeutic. In this report, we use nanoscale AFM-IR spectroscopy to probe the structure of Aβ oligomers and fibrils at the single aggregate level and demonstrate that the main effect of β-carotene towards modulating Aβ aggregation is not to inhibit fibril formation but to alter the secondary structure of the fibrils and promote fibrils that lack the characteristic ordered beta structure.

RevDate: 2023-03-29

Yoo CH, Kim J, Baek HM, et al (2023)

Neurodegenerative Changes in the Brains of the 5xFAD Alzheimer's Disease Model Mice Investigated by High-Field and High-Resolution Magnetic Resonance Imaging and Multi-Nuclei Magnetic Resonance Spectroscopy.

International journal of molecular sciences, 24(6): pii:ijms24065073.

This study aimed to investigate morphological and metabolic changes in the brains of 5xFAD mice. Structural magnetic resonance imaging (MRI) and [1]H magnetic resonance spectroscopy (MRS) were obtained in 10- and 14-month-old 5xFAD and wild-type (WT) mice, while [31]P MRS scans were acquired in 11-month-old mice. Significantly reduced gray matter (GM) was identified by voxel-based morphometry (VBM) in the thalamus, hypothalamus, and periaqueductal gray areas of 5xFAD mice compared to WT mice. Significant reductions in N-acetyl aspartate and elevation of myo-Inositol were revealed by the quantification of MRS in the hippocampus of 5xFAD mice, compared to WT. A significant reduction in NeuN-positive cells and elevation of Iba1- and GFAP-positive cells supported this observation. The reduction in phosphomonoester and elevation of phosphodiester was observed in 11-month-old 5xFAD mice, which might imply a sign of disruption in the membrane synthesis. Commonly reported [1]H MRS features were replicated in the hippocampus of 14-month-old 5xFAD mice, and a sign of disruption in the membrane synthesis and elevation of breakdown were revealed in the whole brain of 5xFAD mice by [31]P MRS. GM volume reduction was identified in the thalamus, hypothalamus, and periaqueductal gray areas of 5xFAD mice.

RevDate: 2023-03-29

Rodríguez-Hidalgo E, García-Alba J, Novell R, et al (2023)

The Global Deterioration Scale for Down Syndrome Population (GDS-DS): A Rating Scale to Assess the Progression of Alzheimer's Disease.

International journal of environmental research and public health, 20(6): pii:ijerph20065096.

The aim of this study is to adapt and validate the global deterioration scale (GDS) for the systematic tracking of Alzheimer's disease (AD) progression in a population with Down syndrome (DS). A retrospective dual-center cohort study was conducted with 83 participants with DS (46.65 ± 5.08 years) who formed the primary diagnosis (PD) group: cognitive stability (n = 48), mild cognitive impairment (n = 24), and Alzheimer's disease (n = 11). The proposed scale for adults with DS (GDS-DS) comprises six stages, from cognitive and/or behavioral stability to advanced AD. Two neuropsychologists placed the participants of the PD group in each stage of the GDS-DS according to cognitive, behavioral and daily living skills data. Inter-rater reliability in staging with the GDS-DS was excellent (ICC = 0.86; CI: 0.80-0.93), and the agreement with the diagnosis categories of the PD group ranged from substantial to excellent with κ values of 0.82 (95% CI: 0.73-0.92) and 0.85 (95% CI: 0.72, 0.99). Performance with regard to the CAMCOG-DS total score and orientation subtest of the Barcelona test for intellectual disability showed a slight progressive decline across all the GDS-DS stages. The GDS-DS scale is a sensitive tool for staging the progression of AD in the DS population, with special relevance in daily clinical practice.

RevDate: 2023-03-29

Lopez-de-Andres A, Jimenez-Garcia R, Zamorano-Leon JJ, et al (2023)

Prevalence of Dementia among Patients Hospitalized with Type 2 Diabetes Mellitus in Spain, 2011-2020: Sex-Related Disparities and Impact of the COVID-19 Pandemic.

International journal of environmental research and public health, 20(6): pii:ijerph20064923.

(1) Background: To assess changes in the prevalence of dementia among patients hospitalized with type 2 diabetes (T2DM), to analyze the effects of dementia on in-hospital mortality (IHM) in this population, to evaluate sex differences, and to determine the impact of the COVID-19 pandemic on these parameters. (2) Methods: We used a nationwide discharge database to select all patients with T2DM aged 60 years or over admitted to Spanish hospitals from 2011 to 2020. We identified those with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). The effect of sex, age, comorbidity, and COVID-19 on the prevalence of dementia subtypes and on IHM was assessed using multivariable logistic regression. (3) Results: We identified 5,250,810 hospitalizations with T2DM. All-cause dementia was detected in 8.31%, AD in 3.00%, and VaD in 1.55%. The prevalence of all subtypes of dementia increased significantly over time. After multivariable adjustment, higher values were observed in women for all-cause dementia (OR 1.34; 95% CI 1.33-1.35), AD (OR 1.6; 95% CI 1.58-1.62), and VaD (OR 1.12; 95% CI 1.11-1.14). However, female sex was a protective factor for IHM in patients with all-cause dementia (OR 0.90; 95% CI 0.89-0.91), AD (OR 0.89; 95% CI 0.86-0.91), and VaD (OR 0.95; 95% CI 0.91-0.99). IHM among patients with dementia remained stable over time, until 2020, when it increased significantly. Higher age, greater comorbidity, and COVID-19 were associated with IHM in all dementia subtypes. (4) Conclusions: The prevalence of dementia (all-cause, AD, and VaD) in men and women with T2DM increased over time; however, the IHM remained stable until 2020, when it increased significantly, probably because of the COVID-19 pandemic. The prevalence of dementia is higher in women than in men, although female sex is a protective factor for IHM.

RevDate: 2023-03-29

Said-Sadier N, Sayegh B, Farah R, et al (2023)

Association between Periodontal Disease and Cognitive Impairment in Adults.

International journal of environmental research and public health, 20(6): pii:ijerph20064707.

INTRODUCTION: Periodontitis is a severe oral infection that can contribute to systemic inflammation. A large body of evidence suggests a role for systemic inflammation in the initiation of neurodegenerative disease. This systematic review synthesized data from observational studies to investigate the association between periodontitis and neuroinflammation in adults.

METHODS AND MATERIALS: A systematic literature search of PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) was performed for studies published from the date of inception up to September 2021. Search terms for the exposure "oral disease" and outcome "dementia", "neuroinflammation" and "cognitive decline" were used. Study selection and data extraction were independently undertaken by two reviewers. The final eligible articles were included only if the exposure is periodontitis and the outcome is cognitive impairment or dementia or a topic related to this condition, and if the study was conducted in an adult population. The quality and risk of bias were assessed by Newcastle Ottawa Scale (NOS). Qualitative synthesis was used to narratively synthesize the results. Six cohort studies, three cross-sectional studies, and two case-control studies met the inclusion criteria. These eleven studies were only narratively synthesized. Meta-analysis was not performed due to the methodological heterogeneity of the studies.

RESULTS: The results of included studies show that chronic periodontitis patients with at least eight years of exposure are at higher risk of developing cognitive decline and dementia. Oral health measures such as gingival inflammation, attachment loss, probing depth, bleeding on probing, and alveolar bone loss are associated with cognitive impairment. The reduction of epidermal growth factor (EGF), interleukin 8 (IL-8), interferon γ-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) in addition to over expression of interleukin 1-β (IL-1β) are significant in patients suffering from cognitive decline with pre-existing severe periodontitis.

CONCLUSIONS: All the included studies show evidence of an association between periodontitis and cognitive impairment or dementia and Alzheimer's disease pathology. Nonetheless, the mechanisms responsible for the association between periodontitis and dementia are still unclear and warrant further investigation.

RevDate: 2023-03-29

Kopel J, Sehar U, Choudhury M, et al (2023)

Alzheimer's Disease and Alzheimer's Disease-Related Dementias in African Americans: Focus on Caregivers.

Healthcare (Basel, Switzerland), 11(6): pii:healthcare11060868.

Alzheimer's disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are chronic illnesses that are highly prevalent in African Americans (AA). AD and ADRD are caused by multiple factors, such as genetic mutations, modifiable and non-modifiable risk factors, and lifestyle. Histopathological, morphological, and cellular studies revealed how multiple cellular changes are implicated in AD and ADRD, including synaptic damage, inflammatory responses, hormonal imbalance, mitochondrial abnormalities, and neuronal loss, in addition to the accumulation of amyloid beta and phosphorylated tau in the brain. The contributions of race, ethnicity, location and socioeconomic status all have a significant impact on the care and support services available to dementia patients. Furthermore, disparities in health care are entangled with social, economic, and environmental variables that perpetuate disadvantages among different groups, particularly African Americans. As such, it remains important to understand how various racial and ethnic groups perceive, access, and experience health care. Considering that the mounting data shows AA may be more susceptible to AD than white people, the demographic transition creates significant hurdles in providing adequate care from family caregivers. Furthermore, there is growing recognition that AD and ADRD pose a significant stress on AA caregivers compared to white people. In this review, we examine the current literature on racial disparities in AD and ADRD, particularly concerning AA caregivers.

RevDate: 2023-03-29

Chehimi SN, Crist RC, BC Reiner (2023)

Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches.

Genes, 14(3): pii:genes14030771.

The development of single-cell and single-nucleus transcriptome technologies is enabling the unraveling of the molecular and cellular heterogeneity of psychiatric disorders. The complexity of the brain and the relationships between different brain regions can be better understood through the classification of individual cell populations based on their molecular markers and transcriptomic features. Analysis of these unique cell types can explain their involvement in the pathology of psychiatric disorders. Recent studies in both human and animal models have emphasized the importance of transcriptome analysis of neuronal cells in psychiatric disorders but also revealed critical roles for non-neuronal cells, such as oligodendrocytes and microglia. In this review, we update current findings on the brain transcriptome and explore molecular studies addressing transcriptomic alterations identified in human and animal models in depression and stress, neurodegenerative disorders (Parkinson's and Alzheimer's disease), schizophrenia, opioid use disorder, and alcohol and psychostimulant abuse. We also comment on potential future directions in single-cell and single-nucleus studies.

RevDate: 2023-03-29

Zajac DJ, Simpson J, Zhang E, et al (2023)

Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer's Disease Neuropathology and Genetics.

Genes, 14(3): pii:genes14030763.

The single nucleotide polymorphisms rs35349669 and rs10933431 within Inositol Polyphosphate-5-Phosphatase D (INPP5D) are strongly associated with Alzheimer's Disease risk. To better understand INPP5D expression in the brain, we investigated INPP5D isoform expression as a function of rs35349669 and rs10933431, as well as Alzheimer's disease neuropathology, by qPCR and isoform-specific primers. In addition, INPP5D allelic expression imbalance was evaluated relative to rs1141328 within exon 1. Expression of INPP5D isoforms associated with transcription start sites in exon 1 and intron 14 was increased in individuals with high Alzheimer's disease neuropathology. In addition, a novel variant with 47bp lacking from exon 12 increased expression in Alzheimer's Disease brains, accounting for 13% of total INPP5D expression, and was found to undergo nonsense-mediated decay. Although inter-individual variation obscured a possible polymorphism effect on INPP5D isoform expression as measured by qPCR, rs35349669 was associated with rs1141328 allelic expression imbalance, suggesting that rs35349669 is significantly associated with full-length INPP5D isoform expression. In summary, expression of INPP5D isoforms with start sites in exon 1 and intron 14 are increased in brains with high Alzheimer's Disease neuropathology, a novel isoform lacking the phosphatase domain was significantly increased with the disease, and the polymorphism rs35349669 correlates with allele-specific full-length INPP5D expression.

RevDate: 2023-03-29

Chakraborty D, Zhuang Z, Xue H, et al (2023)

Deep Learning-Based Feature Extraction with MRI Data in Neuroimaging Genetics for Alzheimer's Disease.

Genes, 14(3): pii:genes14030626.

The prognosis and treatment of patients suffering from Alzheimer's disease (AD) have been among the most important and challenging problems over the last few decades. To better understand the mechanism of AD, it is of great interest to identify genetic variants associated with brain atrophy. Commonly, in these analyses, neuroimaging features are extracted based on one of many possible brain atlases with FreeSurf and other popular software; this, however, may cause the loss of important information due to our incomplete knowledge about brain function embedded in these suboptimal atlases. To address the issue, we propose convolutional neural network (CNN) models applied to three-dimensional MRI data for the whole brain or multiple, divided brain regions to perform completely data-driven and automatic feature extraction. These image-derived features are then used as endophenotypes in genome-wide association studies (GWASs) to identify associated genetic variants. When we applied this method to ADNI data, we identified several associated SNPs that have been previously shown to be related to several neurodegenerative/mental disorders, such as AD, depression, and schizophrenia.

RevDate: 2023-03-29

Custodia A, Aramburu-Núñez M, Rodríguez-Arrizabalaga M, et al (2023)

Biomarkers Assessing Endothelial Dysfunction in Alzheimer's Disease.

Cells, 12(6): pii:cells12060962.

Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial dysfunction as a key player in the cognitive decline course of AD. As a main component of the blood-brain barrier (BBB), the dysfunction of endothelial cells driven by vascular risk factors associated with AD allows the passage of toxic substances to the cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, the levels of several biomarkers are disrupted, such as an increase in adhesion molecules that allow the passage of leukocytes to the cerebral parenchyma, increasing the permeability of the BBB; moreover, other vascular players, including endothelin-1, also mediate artery inflammation. As a consequence of the disruption of the BBB, a progressive neuroinflammatory response is produced that, added to the astrogliosis, eventually triggers neuronal degeneration (possibly responsible for cognitive deterioration). Recently, new molecules have been proposed as early biomarkers for endothelial dysfunction that can constitute new therapeutic targets as well as early diagnostic and prognostic markers for AD.


RJR Experience and Expertise


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.


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.


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.


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.


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.


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.


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.


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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E-mail: RJR8222@gmail.com

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

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )