Pterostilbene Ameliorates Cognitive Impairment in Polycystic Ovary Syndrome Rat Model through Improving Insulin Resistance via the IRS-1/PI3K/Akt/GSK-3ß Pathway: A Comparative Study with Metformin.

Polycystic ovary syndrome (PCOS) is an intricate endocrine disorder that targets millions of women globally. Recent research has drawn attention to its association with cognitive impairment and Alzheimer's disease (AD) risk, yet the exact mechanism remains elusive. This study aimed to explore the potential role of PCOS-associated insulin resistance (IR) and inflammation in linking PCOS to AD pathogenesis. It additionally investigated the therapeutic merits of pterostilbene (PTS) in ameliorating PCOS and associated cognitive deficits in comparison to metformin (MET). Rats were divided into five groups; vehicle group, PTS group [30 mg/kg, per os (p.o.) for 13 days], and the remaining three groups received letrozole (1 mg/kg, p.o. for 21 days) to represent the PCOS, PCOS + MET (300 mg/kg, p.o. for 13 days), and PCOS + PTS groups, respectively. Behavioral tests were conducted, along with a histopathological investigation of brains and ovaries. Assessment of serum hormonal profile and hippocampal IRS-1/PI3K/AKT/GSK-3ß insulin signaling pathway components were performed. PTS rats exhibited improved insulin sensitivity and hormonal profile, besides enhanced neurobehavioral tests performance and histopathological findings. These effects may be attributed to modulation of the IRS-1/PI3K/AKT/GSK-3ß pathway, reducing GSK-3ß activity, and mitigating Tau hyperphosphorylation and Aß accumulation in the brain. Likewise, PTS attenuated nuclear factor kappa B-mediated inflammation and reversed AChE elevation, suggesting multifaceted neuroprotective effects. Comparatively, PTS showed outcomes similar to those of MET in most parameters. The obtained findings validated that dysregulated insulin signaling in PCOS rats detrimentally affects cognitive function, which is halted by PTS, unveiling the potential of PTS as a novel therapy for PCOS and related cognitive deficits.

Tranexamic Acid Administration Does Not Alter Inflammation After Traumatic Brain Injury, Regardless of Timing.

INTRODUCTION: Tranexamic acid (TXA) administered early after traumatic brain injury (TBI) can decrease morbidity and mortality. The purpose of this study is to determine if the timing of TXA administration after TBI affects postinjury inflammatory markers or phosphorylated tau (p-tau) levels within the hippocampus. METHODS: Male mice (9-11 wk) were split into six groups based on injury and timing of TXA administration (n = 5 per group): Sham, TBI-only, 100 mg/kg TXA-only, TBI + TXA 10 min, TBI + TXA 1 h, and TBI + TXA 6 h. Moderate concussive TBI was induced via weight drop. Serum and brain homogenates were collected at 6 and 24 h postinjury and analyzed for 14 inflammatory cytokines via multiplex enzyme-linked immunosorbent assay. Serum was analyzed for glial fibrillary acidic protein levels. Additional cohorts were survived to 30 d for hippocampal p-tau quantification using immunohistochemistry. RESULTS: Serum levels of interleukin (IL) 1ß (IL-1ß), IL-3, IL-12, IL-17, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and regulated on activation, normal T-cell expressed and secreted were elevated in TBI mice compared to sham mice at 24 h. Levels of IL-1ß and monocyte chemoattractant protein-1 were lower in 6-h TXA-treated mice than 1-h TXA-treated mice following TBI. IL-12 and macrophage inflammatory protein-1α levels were decreased in 6-h TXA-treated mice compared to 10-min TXA-treated mice. Administration of TXA at 10 min and 6 h but not 1 h postTBI reduced serum glial fibrillary acidic protein levels compared to TBI-only mice. Hippocampal p-tau accumulation was increased after TBI but not reduced by TXA administration. CONCLUSIONS: Our results demonstrate that neither early nor delayed administration of TXA conveyed significant systemic or cerebral benefit in cytokine levels following TBI. Further research should be conducted to assess blood brain barrier integrity and neurobehavioral recovery following TXA administration postTBI.

The relationship between hypoxia and Alzheimer's disease: an updated review.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and the most prevalent form of dementia. The main hallmarks for the diagnosis of AD are extracellular amyloid-beta (Aß) plaque deposition and intracellular accumulation of highly hyperphosphorylated Tau protein as neurofibrillary tangles. The brain consumes more oxygen than any other organs, so it is more easily to be affected by hypoxia. Hypoxia has long been recognized as one of the possible causes of AD and other neurodegenerative diseases, but the exact mechanism has not been clarified. In this review, we will elucidate the connection between hypoxia-inducible factors-1α and AD, including its contribution to AD and its possible protective effects. Additionally, we will discuss the relationship between oxidative stress and AD as evidence show that oxidative stress acts on AD-related pathogenic factors such as mitochondrial dysfunction, Aß deposition, inflammation, etc. Currently, there is no cure for AD. Given the close association between hypoxia, oxidative stress, and AD, along with current research on the protective effects of antioxidants against AD, we speculate that antioxidants could be a potential therapeutic approach for AD and worth further study.

Development of thresholds and a visualization tool for use of a blood test in routine clinical dementia practice.

INTRODUCTION: We developed a multimarker blood test result interpretation tool for the clinical dementia practice, including phosphorylated (P-)tau181, amyloid-beta (Abeta)42/40, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). METHODS: We measured the plasma biomarkers with Simoa (n = 1199), applied LASSO regression for biomarker selection and receiver operating characteristics (ROC) analyses to determine diagnostic accuracy. We validated our findings in two independent cohorts and constructed a visualization approach. RESULTS: P-tau181, GFAP, and NfL were selected. This combination had area under the curve (AUC) = 83% to identify amyloid positivity in pre-dementia stages, AUC = 87%-89% to differentiate Alzheimer's or controls from frontotemporal dementia, AUC = 74%-76% to differentiate Alzheimer's or controls from dementia with Lewy bodies. Highly reproducible AUCs were obtained in independent cohorts. The resulting visualization tool includes UpSet plots to visualize the stand-alone biomarker results and density plots to visualize the biomarker results combined. DISCUSSION: Our multimarker blood test interpretation tool is ready for testing in real-world clinical dementia settings. HIGHLIGHTS: We developed a multimarker blood test interpretation tool for clinical dementia practice. Our interpretation tool includes plasma biomarkers P-tau, GFAP, and NfL. Our tool is particularly useful for Alzheimer's and frontotemporal dementia diagnosis.

Neurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer's pathology.

A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline in Alzheimer's disease (AD) because tangles correlate anatomically with areas that undergo neuronal loss. We used two-photon longitudinal imaging to directly test this hypothesis and observed the fate of individual neurons in two mouse models. At any time point, neurons without tangles died at >3 times the rate as neurons with tangles. Additionally, prior to dying, they became >20% more distant from neighboring neurons across imaging sessions. Similar microstructural changes were evident in a population of non-tangle-bearing neurons in Alzheimer's donor tissues. Together, these data suggest that nonfibrillar tau puts neurons at high risk of death, and surprisingly, the presence of a tangle reduces this risk. Moreover, cortical microstructure changes appear to be a better predictor of imminent cell death than tangle status is and a promising tool for identifying dying neurons in Alzheimer's.

Story recall performance and AT classification via positron emission tomography: A comparison of logical memory and Craft Story 21.

BACKGROUND: Early detection of Alzheimer's disease (AD) is one of the critical components of the global response to the growing dementia crisis. Analysis of serial position performance in story recall tests has yielded sensitive metrics for the prediction of AD at low cost. In this study, we examined whether serial position markers in two story recall tests (the logical memory test, LMT, and the Craft Story 21 test, CST) were sensitive to cross-sectional biomarker-based assessment of in vivo neuropathology. METHODS: Participants were selected from the Wisconsin Registry of Alzheimer's Prevention (n = 288; WRAP) and the Alzheimer's Disease Research Center (n = 156; ADRC), both from the University of Wisconsin-Madison. Average age at PET was 68.9 (6.7) and 67.0 (8.0), respectively. Data included tau and PiB PET, and LMT for WRAP participants and CST for ADRC participants. Two sets of Bayesian analyses (logistic regressions and ANCOVAs) were conducted within each cohort, separately. RESULTS: Results indicated that the A+T+ classification was best predicted, cross-sectionally, by the recency ratio (Rr), indexing how much of the end of the story was forgotten between initial learning and delayed assessment. Rr outperformed traditional scores and discriminated between A+T+ and A+T-/A-T-, in both cohorts. CONCLUSIONS: Overall, this study confirms that serial position analysis of LMT and CST data, and particularly Rr as an index of recency loss, is a valuable tool for the identification of in vivo tau pathology in individuals free of dementia. Diagnostic considerations are discussed.

Explore the Role of Frailty as a Contributor to the Association Between AT(N) Profiles and Cognition in Alzheimer's Disease.

Background: The relationship between Alzheimer's disease (AD)-related pathology and cognition was not exactly consistent. Objective: To explore whether the association between AD pathology and cognition can be moderated by frailty. Methods: We included 1711 participants from the Alzheimer's Disease Neuroimaging Initiative database. Levels of cerebrospinal fluid amyloid-ß, p-tau, and t-tau were identified for AD-related pathology based on the amyloid-ß/tau/neurodegeneration (AT[N]) framework. Frailty was measured using a modified Frailty Index-11 (mFI-11). Regression and interaction models were utilized to assess the relationship among frailty, AT(N) profiles, and cognition. Moderation models analyzed the correlation between AT(N) profiles and cognition across three frailty levels. All analyses were corrected for age, sex, education, and APOEɛ4 status. Results: In this study, frailty (odds ratio [OR] = 1.71, p < 0.001) and AT(N) profiles (OR = 2.00, p < 0.001) were independently associated with cognitive status. The model fit was improved when frailty was added to the model examining the relationship between AT(N) profiles and cognition (p < 0.001). There was a significant interaction between frailty and AT(N) profiles in relation to cognitive status (OR = 1.12, pinteraction = 0.028). Comparable results were obtained when Mini-Mental State Examination scores were utilized as the measure of cognitive performance. The association between AT(N) profiles and cognition was stronger with the levels of frailty. Conclusions: Frailty may diminish patients' resilience to AD pathology and accelerate cognitive decline resulting from abnormal AD-related pathology. In summary, frailty contributes to elucidating the relationship between AD-related pathology and cognitive impairment.

Clinical significance of plasma candidate biomarkers of Alzheimer's Disease.

The number of patients with Alzheimer's Disease (AD) has increased rapidly in recent decades. AD is a complex progressive neurodegenerative disease affecting c.14 million patients in Europe and the United States. The hallmarks of this disease are neurotic plaques composed of the amyloid-ß (Aß) peptide and neurofibrillary tangles formed of hyperphosphorylated tau protein (pTau). To date, four CSF biomarkers: amyloid beta 42 (Aß42), Aß42/40 ratio, Tau protein, and Tau phosphorylated at threonine 181 (pTau181) have been validated as core neurochemical AD biomarkers. Imaging biomarkers are valuable for AD diagnosis, although they suffer from limitations in their cost and accessibility, while CSF biomarkers require lumbar puncture. Thus, there is an urgent need for alternative, less invasive and more cost-effective biomarkers capable of diagnosing and monitoring AD progression in a clinical context, as well as expediting the development of new therapeutic strategies. This review assesses the potential clinical significance of plasma candidate biomarkers in AD diagnosis. We conclude that these proteins might hold great promise in identifying the pathological features of AD. However, the future implementation process, and validation of the assays' accuracy using predefined cut-offs across more diverse patient populations, are crucial in establishing their utility in daily practice.

Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease.

INTRODUCTION: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aß42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.Supports further clinical development of PB and TURSO in neurodegenerative diseases.

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

BACKGROUND: We 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 Aß/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. METHODS: To 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. RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aß/tau fibrillation, Aß 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 s100ß 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. CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aß/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

Exploring the molecular mechanisms underlying neuroprotective effect of ellagic acid in okadaic acid-induced Alzheimer's phenotype.

Pomegranate polyphenol ellagic acid has medicinal potential in neurodegenerative disorders. The advantageous effect of this polyphenol in improving cognition in okadaic acid (OA)-instigated murine model with unraveling some modes of its action was assessed. Rats received ICV okadaic acid (OA) and post-treated with oral ellagic acid for 3 weeks (25 and 100 mg/kg/day). Cognition was analyzed in behavioral tasks besides assessment of oxidative, apoptotic, and inflammatory factors in addition to hippocampal histochemical analysis. Ellagic acid at a dose of 100 mg/kg properly attenuated cognitive abnormalities in novel object recognition (NOR), Y maze, and Barnes maze tests. Additionally, ellagic acid diminished hippocampal changes of malondialdehyde (MDA), protein carbonyl, reactive oxygen species (ROS), glutathione (GSH), glutathione peroxidase, superoxide dismutase (SOD), apoptotic factors caspases 1 and 3, tumor necrosis factor α (TNFα), and acetylcholinesterase (AChE) and beta secretase 1 (BACE 1) besides reversal of AMP-activated protein kinase (AMPK) and hyperphosphorylated tau (p-tau). Moreover, lower glial fibrillary acidic protein (GFAP) and less injury of hippocampal CA1 pyramidal neurons were observed upon ellagic acid. To conclude, neuroprotective potential of ellagic acid was shown which is somewhat attributable to its reversal of oxidative, apoptotic, and neuroinflammatory events in addition to proper regulation of AMPK and p-tau.

Pooling Alzheimer's disease clinical trial data to develop personalized medicine approaches is easier said than done: A proof-of-principle study and call to action.

With the advent of the first generation of disease-modifying treatments for Alzheimer's disease, it is clearer now more than ever that the field needs to move toward personalized medicine. Pooling data from past trials may help identify subgroups most likely to benefit from specific treatments and thus inform future trial design. In this perspective, we report on our effort to pool data from past Alzheimer's disease trials to identify patients most likely to respond to different treatments. We delineate challenges and hurdles, from our proof-of-principle study, for which we requested access to trial datasets from various pharmaceutical companies and encountered obstacles in the process of arranging data-sharing agreements through legal departments. Six phase I-III trials from three sponsors provided access to their data (total n = 3170), which included demographic information, vital signs, primary and secondary endpoints, and in a small subset, cerebrospinal fluid amyloid (n = 165, 5.2%) and tau (n = 212, 6.7%). Data could be analyzed only within specific data access platforms, limiting potential harmonization with data provided through other platforms. Limited overlap in terms of outcome measures, clinical and biological information hindered analyses. Thus, while it is a commendable advancement that (some) trials now allow researchers to study their data, we conclude that gaining access to past trial datasets is complicated, frustrating the field's communal effort to find the best treatments for the right individuals. We provide a plea to promote harmonization and open access to data, by urging trial sponsors and the academic research community alike to remove barriers to data access and improve collaboration through practicing open science and harmonizing outcome measures, to allow investigators to learn all there is to learn from past failures and successes. HIGHLIGHTS: Pooling data from past Alzheimer's disease clinical trials may help identify subgroups most likely to benefit from specific treatments and may help inform future trial design.Accessing past trial datasets is complicated, frustrating the field's communal effort to find the best treatments for the right individuals.We urge trial sponsors and the academic research community to remove data access barriers and improve collaboration through practicing open science and harmonizing outcome measures.

Mathematical modelling of Alzheimer's disease biomarkers: Targeting Amyloid beta, Tau protein, Apolipoprotein E and Apoptotic pathways.

Introduction: The kinetics of brain cell death in Alzheimer's disease (AD) is being studied using mathematical models. These mathematical models utilize techniques like differential equations, stochastic processes, and network theory to explore crucial signalling pathways and interactions between different cell types. One crucial area of research is the intentional cell death known as apoptosis, which is crucial for the nervous system. The main purpose behind the mathematical modelling of this is for identification of which biomarkers and pathways are most influential in the progression of AD. In addition, we can also predict the natural history of the disease, by which we can make early diagnosis. Mathematical modelling of AD: Current mathematical models include the Apolipoprotein E (APOE) Gene Model, the Tau Protein Kinetics Model, and the Amyloid Beta Peptide Kinetic Model. The Bcl-2 and Bax apoptosis theories postulate that the balance of pro- and anti-apoptotic proteins in cells determines whether a cell experiences apoptosis, where the Bcl-2 model, depicts the interaction of pro- and anti-apoptotic proteins, it is also being used in research on cell death in a range of cell types, including neurons and glial cells. How peptides are produced and eliminated in the brain is explained by the Amyloid beta Peptide (Aß) Kinetics Model. The tau protein kinetics model focuses on production, aggregation, and clearance of tau protein processes, which are hypothesized to be involved in AD. The APOE gene model investigates the connection between the risk of Alzheimer's disease and the APOE gene. These models have been used to predict how Alzheimer's disease would develop and to evaluate how different inhibitors will affect the illness's course. Conclusion: These mathematical models reflect physiological meaningful characteristics and demonstrates robust fits to training data. Incorporating biomarkers like Aß, Tau, APOE and markers of neuronal loss and cognitive impairment can generate sound predictions of biomarker trajectories over time in Alzheimer's disease.

Induction of tau pathology and motor dysfunction in mice by urinary exosomes from progressive supranuclear palsy patients.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by the presence of hyperphosphorylated and misfolded tau aggregates in neurons and glia. Recent studies have illuminated the prion-like cell-to-cell propagation of tau via exosomes. Recognizing the potential significance of excretion through urine as a crucial pathway for eliminating pathological tau from the central nervous system, this study aimed to investigate whether exosomes derived from the urine of PSP-Richardson's syndrome (PSP-RS) patients can elicit tau pathology and PSP-like symptoms in mice. METHODS: Urinary exosomes obtained from PSP-RS patients and normal controls (NCs) were stereotactically injected into the bilateral globus pallidus of mouse brains. Behavioral analyses were conducted every 3 months post-injection. After 6 months, mice were sacrificed for pathological evaluation. RESULTS: Elevated levels of phosphorylated tau and neural cell markers were observed in urinary exosomes from PSP-RS patients compared to NCs. At the 6-month mark post-injection, tau inclusions were evident in the brains of mice receiving urinary exosomes from PSP-RS patients, with widespread distribution in both injection sites and distant brain regions (cortex, hippocampus, and substantia nigra). Tau pathology manifested in neurons and astrocytes. Moreover, mice injected with urinary exosomes from PSP-RS patients exhibited impaired motor coordination and balance, mirroring PSP motor symptoms. CONCLUSION: Our findings indicate that urinary exosomes from PSP-RS patients can induce tau pathology and trigger PSP-like motor symptoms in mice. This leads to the hypothesis that exosomes may play a role in the pathogenesis of PSP.

The Alzheimer's Disease Neuroimaging Initiative Clinical Core.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Clinical Core is responsible for coordination of all clinical activities at the ADNI sites, including project management, regulatory oversight, and site management and monitoring, as well as the collection of all clinical data and management of all study data. The Clinical Core is also charged with determining the clinical classifications and criteria for enrollment in evolving AD trials and enabling the ongoing characterization of the cross-sectional features and longitudinal trajectories of the ADNI cohorts with application of these findings to optimal clinical trial designs. More than 2400 individuals have been enrolled in the cohorts since the inception of ADNI, facilitating refinement of our understanding of the AD trajectory and allowing academic and industry investigators to model therapeutic trials across the disease spectrum from the presymptomatic stage through dementia. HIGHLIGHTS: Since 2004, the Alzheimer's Disease Neuroimaging Initiative (ADNI) Clinical Core has overseen the enrollment of > 2400 participants with mild cognitive impairment, mild Alzheimer's disease (AD) dementia, and normal cognition. The longitudinal dataset has elucidated the full cognitive and clinical trajectory of AD from its presymptomatic stage through the onset of dementia. The ADNI data have supported the design of most major trials in the field.

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 (Aß) 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 Aß, preserving brain health, and slowing AD pathology progression.

Cytoarchitectonic gradients of laminar degeneration in behavioural variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was relatively uniform along the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau versus bvFTD-TDP (p=0.039). Using a ratio of SMI32-ir to model known long-range connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio in bvFTD-tau versus bvFTD-TDP (p=0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau versus bvFTD-TDP (p=0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.

REELIN ameliorates Alzheimer's disease, but how?

Alzheimer's disease (AD) is the most prevalent type of dementia; therefore, there is a high demand for therapeutic medication targeting it. In this context, extensive research has been conducted to identify molecular targets for drugs. AD manifests through two primary pathological signs: senile plaques and neurofibrillary tangles, caused by accumulations of amyloid-beta (Aß) and phosphorylated tau, respectively. Thus, studies concerning the molecular mechanisms underlying AD etiology have primarily focused on Aß generation and tau phosphorylation, with the anticipation of uncovering a signaling pathway impacting these molecular processes. Over the past two decades, studies using not only experimental model systems but also examining human brains have accumulated fragmentary evidences suggesting that REELIN signaling pathway is deeply involved in AD. Here, we explore REELIN signaling pathway and its involvement in memory function within the brain and review studies investigating molecular connections between REELIN signaling pathway and AD etiology. This review aims to understand how the manipulation (activation) of this pathway might ameliorate the disease's etiology.

Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease.

Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Aß) and Tau proteins, neuroinflammation, metabolic changes and neuronal death. Reactive astrocytes participate in these pathophysiological processes by releasing pro-inflammatory molecules and recruiting the immune system, which further reinforces inflammation and contributes to neuronal death. Besides these neurotoxic effects, astrocytes can protect neurons by providing them with high amounts of lactate as energy fuel. Astrocytes rely on aerobic glycolysis to generate lactate by reducing pyruvate, the end product of glycolysis, through lactate dehydrogenase. Consequently, limited amounts of pyruvate enter astrocytic mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to be oxidized. The MPC is a heterodimer composed of two subunits MPC1 and MPC2, the function of which in astrocytes has been poorly investigated. Here, we analyzed the role of the MPC in the pathogeny of AD, knowing that a reduction in overall glucose metabolism has been associated with a drop in cognitive performances and an accumulation of Aß and Tau. We generated 3xTgAD mice in which MPC1 was knocked-out in astrocytes specifically and focused our study on the biochemical hallmarks of the disease, mainly Aß and neurofibrillary tangle production. We show that inhibition of the MPC before the onset of the disease significantly reduces the quantity of Aß and Tau aggregates in the brain of 3xTgAD mice, suggesting that acting on astrocytic glucose metabolism early on could hinder the progression of the disease.

Synthesis and Evaluation of Chloride-Substituted Ramalin Derivatives for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer's disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.