Alzheimer's Disease Pathology Research Articles

Network Pharmacology and Molecular Docking Perspectives into Lignans for Alzheimer's Disease Treatment

Alzheimer’s Disease (AD) is a debilitating neurodegenerative condition with limited treatment options. Lignans, a class of naturally occurring polyphenols found in various plants, have been shown to have the potential to modulate pathways associated with AD pathology. In this study, we used network pharmacology and molecular docking to investigate the therapeutic potential of lignans against AD by targeting specific proteins involved in disease progression. Our established interaction network includes key proteins such as EGFR, HSP90AA1, BCL2, HSP90AB1, IL6, JUN, ESR1, PIK3CA, ERBB2, and PIK3R1. Molecular docking studies have revealed how lignans interact with these proteins and highlighted their potential to influence AD through mechanisms such as inflammation modulation, apoptosis regulation, and signal transduction pathways. The results suggest that lignans have significant binding abilities to these targets, potentially inhibiting their activity and thus alleviating AD symptoms by reducing amyloid-beta accumulation and tau phosphorylation. These findings support the viability of lignans as a basis for the development of new AD therapies and call for further in vivo studies to confirm their efficacy and safety. This integrated approach underscores the value of combining network pharmacology and molecular docking in the search for new therapeutic agents against complex diseases such as AD.

Activation of multifunctional DNA repair APE1/Ref-1 enzyme by the dietary phytochemical Ferulic acid protects human neuroblastoma SH-SY5Y cells against Aβ(25–35)-induced oxidative stress and inflammatory responses

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder associated with the amyloid beta (Aβ) and tau hallmarks. The molecular insights into how neuroinflammation is initially triggered and how it affects neuronal cells are yet at the age of infancy. In this study, SH-SY5Y cells were used as a model for neurons by differentiating and were co-cultured with differentiated THP1 cells (microglia model) as well as treated with Aβ(25–35) and with antioxidant FA to study inflammatory, oxidative stress responses and their effects on co-cultured neurons. Neurons co-cultured with microglial cells showed pronounced increase in ROS levels, NOS expression, truncated N-terminal form (34 kDa) of APE1 expression and AIF’s translocation in the nucleus. The pre-treatment of FA, on the other hand reversed these effects. It was further evaluated how FA/Aβ treatment altered microglial phenotype that in turn affected the neurons. Microglial cells showed M1 phenotype upon Aβ(25–35) stress, while FA induced M2 phenotype against Aβ stress, suggesting that FA alleviated Aβ induced phenotype and its associated effects in the co-cultured neurons by altering the phenotype of microglial cells and induced expression of full length (37 kDa) APE1 enzyme and inhibiting AIF’s nuclear translocation, thus inhibiting apoptosis. This is the first study that revealed Aβ induced cleavage of APE1 enzyme in differentiated neurons, suggesting that APE1 may be the potential early target of Aβ that loses its function and exacerbates AD pathology. FA activated a fully functional form of APE1 against Aβ stress. The impaired function of APE1 could be the initial mechanism by which Aβ induces oxidative and inflammatory responses and dietary phytochemical FA can be a potential therapeutic strategy in managing the disease by activating APE1 that not only repairs oxidative DNA base damage but also maintains mitochondrial function and alleviates neuroinflammatory responses.

Soluble TGF-β decoy receptor TGFBR3 exacerbates Alzheimer's disease pathology by modifying microglial function.

Alzheimer's disease (AD) is a major cause of progressive dementia characterized by memory loss and progressive neurocognitive dysfunction. However, the molecular mechanisms are not fully understood. To elucidate the molecular mechanism contributing to AD, an integrated analytical workflow was deployed to identify pivotal regulatory target within the RNA-sequencing (RNA-seq) data of the temporal cortex from AD patients. Soluble transforming growth factor beta receptor 3 (sTGFBR3) was identified as a critical target in AD, which was abnormally elevated in AD patients and AD mouse models. We then demonstrated that sTGFBR3 deficiency restored spatial learning and memory deficits in amyloid precursor protein (APP)/PS1 and streptozotocin (STZ)-induced neuronal impairment mice after its expression was disrupted by a lentiviral (LV) vector expressing shRNA. Mechanistically, sTGFBR3 deficiency augments TGF-β signaling and suppressing the NF-κB pathway, thereby reduced the number of disease-associated microglia (DAMs), inhibited proinflammatory activity and increased the phagocytic activity of DAMs. Moreover, sTGFBR3 deficiency significantly mitigated acute neuroinflammation provoked by lipopolysaccharide (LPS) and alleviated neuronal dysfunction induced by STZ. Collectively, these results position sTGFBR3 as a promising candidate for therapeutic intervention in AD.

Neuroimaging correlates of Alzheimer's disease biomarker concentrations in a racially diverse high-risk cohort of middle-aged adults.

In this study, we investigated biomarkers in a midlife, racially diverse, at-risk cohort to facilitate early identification and intervention. We examined neuroimaging measures, including resting state functional magnetic resonance imaging (fMRI), white matter hyperintensity vo (WMH), and hippocampal volumes, alongside cerebrospinal fluid (CSF) markers. Our data set included 76 cognitively unimpaired, middle-aged, Black Americans (N=29, F/M=17/12) and Non-Hispanic White (N=47, F/M=27/20) individuals. We compared cerebrospinal fluid phosphorylated tau141 and amyloid beta (Aβ)42 to fMRI default mode network (DMN) subnetwork connectivity, WMH volumes, and hippocampal volumes. Results revealed a significant race × Aβ42 interaction in Black Americans: lower Aβ42 was associated with reduced DMN connectivity and increased WMH volumes regions but not in non-Hispanic White individuals. Our findings suggest that precuneus DMN connectivity and temporal WMHs may be linked to Alzheimer's disease risk pathology during middle age, particularly in Black Americans. Cerebrospinal fluid (CSF) amyloid beta (Aβ)42 relates to precuneus functional connectivity in Black, but not White, Americans. Higher white matter hyperintensity volume relates to lower CSF Aβ42 in Black Americans. Precuneus may be a hub for early Alzheimer's disease pathology changes detected by functional connectivity.

Amyloid beta 1-40 and 1-42 fibril ratios and maturation level cause conformational differences with minimal impact on autophagy and cytotoxicity.

The amyloid β (Aβ) peptide has a central role in Alzheimer's disease (AD) pathology. The peptide length can vary between 37 and 49 amino acids, with Aβ1-42 being considered the most disease-related length. However, Aβ1-40 is also found in Aβ plaques and has shown to form intertwined fibrils with Aβ1-42. The peptides have previously also shown to form different fibril conformations, proposed to be related to disease phenotype. To conduct more representative invitro experiments, it is vital to uncover the impact of different fibril conformations on neurons. Hence, we fibrillized different Aβ1-40:42 ratios in concentrations of 100:0, 90:10, 75:25, 50:50, 25:75, 10:90 and 0:100 for either 24 h (early fibrils) or 7 days (aged fibrils). These were then characterized based on fibril width, LCO-staining and antibody-staining. We further challenged differentiated neuronal-like SH-SY5Y human cells with the different fibrils and measured Aβ content, cytotoxicity and autophagy function at three different time-points: 3, 24, and 72 h. Our results revealed that both Aβ1-40:42 ratio and fibril maturation affect conformation of fibrils. We further show the impact of these conformation changes on the affinity to commonly used Aβ antibodies, primarily affecting Aβ1-40 rich aggregates. In addition, we demonstrate uptake of the aggregates by neuronally differentiated human cells, where aggregates with higher Aβ1-42 ratios generally caused higher cellular levels of Aβ. These differences in Aβ abundance did not cause changes in cytotoxicity nor in autophagy activation. Our results show the importance to consider conformational differences of Aβ fibrils, as this can have fundamental impact on Aβ antibody detection. Overall, these insights underline the need for further exploration of the impact of conformationally different fibrils and the need to reliably produce disease relevant Aβ aggregates.

Multiple Transcriptomic Analyses Explore Potential Synaptic Biomarker Rabphilin-3A for Alzheimer's Disease

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder afflicting the elderly population worldwide. The identification of potential gene candidates for AD holds promises for diagnostic biomarkers and therapeutic targets. Employing a comprehensive strategy, this study integrated transcriptomic data from diverse data sources, including microarray and single-cell datasets from blood and tissue samples, enabling a detailed exploration of gene expression dynamics. Through this thorough investigation, 19 notable candidate genes were found with consistent expression changes across both blood and tissue datasets, suggesting their potential as biomarkers for AD. In addition, single cell sequencing analysis further highlighted their specific expression in excitatory and inhibitory neurons, the primary functional units in the brain, underscoring their relevance to AD pathology. Moreover, the functional enrichment analysis revealed that three of the candidate genes were downregulated in synaptic signaling pathway. Further validation experiments significantly showed reduced levels of rabphilin-3A (RPH3A) in 3xTg-AD model mice, implying its role in disease pathogenesis. Given its role in neurotransmitter exocytosis and synaptic function, further investigation into RPH3A and its interactions with neurotrophic proteins may provide valuable insights into the complex molecular mechanisms underlying synaptic dysfunction in AD.

Androgen deprivation exacerbates AD pathology by promoting the loss of microglia in an age-dependent manner

AimsMicroglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD. Methods and key findingsTo create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aβ) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aβ plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aβ1–42-induced apoptosis. SignificanceThese findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.

The dopamine analogue CA140 alleviates AD pathology, neuroinflammation, and rescues synaptic/cognitive functions by modulating DRD1 signaling or directly binding to Abeta

BackgroundWe recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer’s disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown.MethodsTo investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted.ResultsIn aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling.ConclusionsOur results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

Myo-inositol and total NAA in the hippocampus are linked to CSF tau pathology in cognitively normal older adults.

Understanding relationships between in vivo neurometabolic changes and Alzheimer's disease (AD) pathology in the hippocampus, a region vulnerable to early changes in AD, will support early diagnosis. Two studies using 1 H-MRS examined concentrations of myo-inositol (MI), total creatine (tCr) and total NAA (tNAA) in the hippocampus. The first study compared hippocampal metabolite concentrations in healthy young and older adults and the second study assessed relationships between hippocampal metabolites and cerebrospinal fluid (CSF) measurements of Aβ42, phosphotau 181 (pTau181), and total tau (t-Tau) while adjusting for demographic covariates and spectral characteristics (linewidth, signal- to-noise ratio) in a separate group of older adults ranging from cognitively normal (CN) to AD-dementia. Hippocampal MI, but not tCr or tNAA, was increased in cognitively normal older versus young adults. Within the second older adult group, MI and tNAA, but not tCr, were linked to increases in CSF pTau181 and t-Tau, but not Aβ42. Tau deposition in cognitively normal individuals is associated with biochemical changes related to glial reactivity and neural integrity in the hippocampus.

Mechanisms of mitophagy and oxidative stress in cerebral ischemia-reperfusion, vascular dementia, and Alzheimer's disease.

Neurological diseases have consistently represented a significant challenge in both clinical treatment and scientific research. As research has progressed, the significance of mitochondria in the pathogenesis and progression of neurological diseases has become increasingly prominent. Mitochondria serve not only as a source of energy, but also as regulators of cellular growth and death. Both oxidative stress and mitophagy are intimately associated with mitochondria, and there is mounting evidence that mitophagy and oxidative stress exert a pivotal regulatory influence on the pathogenesis of neurological diseases. In recent years, there has been a notable rise in the prevalence of cerebral ischemia/reperfusion injury (CI/RI), vascular dementia (VaD), and Alzheimer's disease (AD), which collectively represent a significant public health concern. Reduced levels of mitophagy have been observed in CI/RI, VaD and AD. The improvement of associated pathology has been demonstrated through the increase of mitophagy levels. CI/RI results in cerebral tissue ischemia and hypoxia, which causes oxidative stress, disruption of the blood-brain barrier (BBB) and damage to the cerebral vasculature. The BBB disruption and cerebral vascular injury may induce or exacerbate VaD to some extent. In addition, inadequate cerebral perfusion due to vascular injury or altered function may exacerbate the accumulation of amyloid β (Aβ) thereby contributing to or exacerbating AD pathology. Intravenous tissue plasminogen activator (tPA; alteplase) and endovascular thrombectomy are effective treatments for stroke. However, there is a narrow window of opportunity for the administration of tPA and thrombectomy, which results in a markedly elevated incidence of disability among patients with CI/RI. It is regrettable that there are currently no there are still no specific drugs for VaD and AD. Despite the availability of the U.S. Food and Drug Administration (FDA)-approved clinical first-line drugs for AD, including memantine, donepezil hydrochloride, and galantamine, these agents do not fundamentally block the pathological process of AD. In this paper, we undertake a review of the mechanisms of mitophagy and oxidative stress in neurological disorders, a summary of the clinical trials conducted in recent years, and a proposal for a new strategy for targeted treatment of neurological disorders based on both mitophagy and oxidative stress.

Urinary AD7c-NTP is Associated With Cognitive Recovery After Ischemic Stroke.

Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) is regarded as a biomarker for β-amyloid protein deposition in Alzheimer disease (AD). The value of AD7c-NTP in predicting post-stroke cognitive recovery was worth exploring. In total, 224 patients with first-ever stroke were enrolled in this retrospective study. Cognitive assessment was evaluated by Mini-Mental State Examination (MMSE), and cognitive improvement was defined as MMSE scores ≥27 or 4-score elevation at 3-month follow-up after stroke. The AD7c-NTP level was 0.68±0.40ng/mL in the 135 patients with cognitive improvement, while the AD7c-NTP level was 1.49±0.99ng/mL in the 89 patients without improvement ( P <0.001). Those displaying better cognitive recovery also had younger ages, higher MMSE scores, and lower NIHSS scores on admission. In multivariable logistic regression analysis, AD7c-NTP concentration (OR=9.14, 95% CI: 4.52-18.49, P <0.001), age (OR=1.04, 95% CI: 1.01-1.08, P =0.012), and NIHSS score on admission (OR=1.17, 95% CI: 1.07-1.28, P <0.001) remained the independent risk factors affecting cognitive recovery. The area under the receiver operating characteristics curve for AD7c-NTP in predicting unfavorable cognitive function was 0.80 (sensitivity: 0.73 and specificity: 0.84). Urinary AD7c-NTP is a valuable biomarker associated with post-stroke cognitive recovery. It might be adopted to discriminate coexisting AD pathology from vascular cognitive impairment.

Amyloid, Tau, and APOE in Alzheimer's Disease: Impact on White Matter Tracts.

Alzheimer's disease (AD) is characterized by cognitive decline and memory loss due to the abnormal accumulation of amyloid-beta (Aβ) plaques and tau tangles in the brain; its onset and progression also depend on genetic factors such as the apolipoprotein E (APOE) genotype. Understanding how these factors affect the brain's neural pathways is important for early diagnostics and interventions. Tractometry is an advanced technique for 3D quantitative assessment of white matter tracts, localizing microstructural abnormalities in diseased populations in vivo. In this work, we applied BUAN (Bundle Analytics) tractometry to 3D diffusion MRI data from 730 participants in ADNI3 (phase 3 of the Alzheimer's Disease Neuroimaging Initiative; age range: 55-95 years, 349M/381F, 214 with mild cognitive impairment, 69 with AD, and 447 cognitively healthy controls). Using along-tract statistical analysis, we assessed the localized impact of amyloid, tau, and APOE genetic variants on the brain's neural pathways. BUAN quantifies microstructural properties of white matter tracts, supporting along-tract statistical analyses that identify factors associated with brain microstructure. We visualize the 3D profile of white matter tract associations with tau and amyloid burden in Alzheimer's disease; strong associations near the cortex may support models of disease propagation along neural pathways. Relative to the neutral genotype, APOE ϵ3/ϵ3, carriers of the AD-risk conferring APOE ϵ4 genotype show microstructural abnormalities, while carriers of the protective ϵ2 genotype also show subtle differences. Of all the microstructural metrics, mean diffusivity (MD) generally shows the strongest associations with AD pathology, followed by axial diffusivity (AxD) and radial diffusivity (RD), while fractional anisotropy (FA) is typically the least sensitive metric. Along-tract microstructural metrics are sensitive to tau and amyloid accumulation, showing the potential of diffusion MRI to track AD pathology and map its impact on neural pathways.

The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain.

Deposition of amyloid-β (Aβ) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer's disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aβ degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aβ-degrading enzyme neprilysin and reduced the amount of Aβ deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aβ deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region-specific, neprilysin-dependent degradation of Aβ, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.

The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau.

Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2. We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor). The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect. This study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease

Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.

Brain-Gut and Microbiota-Gut-Brain Communication in Type-2 Diabetes Linked Alzheimer's Disease.

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer's disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer's Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid β (Aβ), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed.

Edaravone N-benzyl pyridinium derivatives: BACE-1 inhibition, kinetics and in silico binding pose determination

BACE-1 plays a pivotal role in the production of β-amyloid (Aβ) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC50 = 44.10 µM - 123.70 µM) and obtained IC50 values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC50 = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC50 of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

Alzheimer's Disease Related Biomarkers Were Associated with Amnestic Cognitive Impairment in Parkinson's Disease: A Cross-Sectional Cohort Study.

Cognitive impairment is common in patients with Parkinson's disease (PD) and occurs through multiple mechanisms, including Alzheimer's disease (AD) pathology and the involvement of α-synucleinopathies. We aimed to investigate the pathological biomarkers of both PD and AD in plasma and neuronal extracellular vesicles (EVs) and their association with different types of cognitive impairment in PD patients. A total of 122 patients with PD and 30 healthy controls were included in this cross-sectional cohort study between March 2021 and July 2023. Non-dementia PD patients were divided into amnestic and non-amnestic groups according to the memory domain of a neuropsychological assessment. Plasma and neuronal EV biomarkers, including α-synuclein (α-syn), beta-amyloid (Aβ), total tau (T-tau), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP), were measured using a single-molecule array and a chemiluminescence immunoassay, respectively. Neuronal EV but not plasma α-syn levels, were significantly increased in PD as compared to healthy controls, and they were positively associated with UPDRS part III scores and the severity of cognitive impairment. A lower plasma Aβ42 level and higher neuronal EV T-tau level were found in the amnestic PD group compared to the non-amnestic PD group. The results of the current study demonstrate that neuronal EV α-syn levels can be a sensitive biomarker for assisting in the diagnosis and disease severity prediction of PD. Both AD and PD pathologies are important factors in cognitive impairment associated with PD, and AD pathologies are more involved in amnestic memory deficit in PD.

Biomarkers of sleep-wake disturbance as predictors of cognitive decline and accelerated disease progression.

In older adults, where sleep disturbances and cognitive impairment are common, mounting evidence suggests a potential connection between sleep and cognitive function, highlighting the significance of utilizing sleep as a biomarker for early detection of cognitive impairment to improve clinical outcomes in a noninvasive, cost-effective manner. This review describes the relationship between sleep and cognitive function in older adults, encompassing both subjective and objective measures of sleep quality, duration, architecture, and sleep-disordered breathing. The authors consider the directionality of the associations observed in prospective and cross-sectional studies, exploring whether sleep disturbances precede cognitive decline or vice versa. Furthermore, they discuss the potential bidirectional relationships between sleep and Alzheimer's disease (AD) risks in older adults while also examining the neurodegenerative pathways of this relationship. Routine sleep monitoring in primary care settings has the potential to bolster early detection and treatment of sleep disturbance, and by extension, reduce the risk of dementia. Improving sleep assessment tools, such as wearables, provide scalable alternatives to traditional methods like polysomnography, potentially enabling widespread monitoring of sleep characteristics. Standardized measurement and inclusive participant recruitment are needed to enhance generalizability, while longitudinal studies are essential to understand the interaction between sleep and AD pathology.

Hydrazides as Inhibitors of Histone Deacetylases.

In this Perspective, we have brought together available biological evidence on hydrazides as histone deacetylase inhibitors (HDACis) and as a distinct type of Zn-binding group (ZBG) to be reviewed for the first time in the literature. N-Alkyl hydrazides have transformed the field, providing innovative and practical chemical tools for selective and effective inhibition of specific histone deacetylase (HDAC) enzymes, in addition to the usual hydroxamic acid and o-aminoanilide ZBG-bearing HDACis. This has enabled efficient targeting of neurodegenerative diseases such as Alzheimer's disease, cancer, cardiovascular diseases, and protozoal pathologies.