Neurofibrillary Tangles Research Articles

Molecular docking studies and molecular dynamic simulation analysis: To identify novel ATP-competitive inhibition of Glycogen synthase kinase-3β for Alzheimer’s disease

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

Vascular Function and Ion Channels in Alzheimer's Disease.

This review paper explores the critical role of vascular ion channels in the regulation of cerebral artery function and examines the impact of Alzheimer's disease (AD) on these processes. Vascular ion channels are fundamental in controlling vascular tone, blood flow, and endothelial function in cerebral arteries. Dysfunction of these channels can lead to impaired cerebral autoregulation, contributing to cerebrovascular pathologies. AD, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, has been increasingly linked to vascular abnormalities, including altered vascular ion channel activity. Here, we briefly review the role of vascular ion channels in cerebral blood flow control and neurovascular coupling. We then examine the vascular defects in AD, the current understanding of how AD pathology affects vascular ion channel function, and how these changes may lead to compromised cerebral blood flow and neurodegenerative processes. Finally, we provide future perspectives and conclusions. Understanding this topic is important as ion channels may be potential therapeutic targets for improving cerebrovascular health and mitigating AD progression.

Thyroid Hormone and Alzheimer's: Bridging Epidemiology to Mechanism.

The identification of critical factors that can worsen the mechanisms contributing to the pathophysiology of Alzheimer's is paramount. Thyroid hormones (TH) fit this criterion. Epidemiological studies have identified an association between altered circulating TH levels and Alzheimer's. The study of human and animal models indicates that TH can affect all the main cellular, molecular, and genetic mechanisms known as hallmarks of Alzheimer's. This is true not only for the excessive production in the brain of protein aggregates leading to amyloid plaques and neurofibrillary tangles but also for the clearance of these molecules from the brain parenchyma via the blood-brain barrier and for the escalated process of neuroinflammation-and even for the effects of carrying Alzheimer's-associated genetic variants. Suboptimal TH levels result in a greater accumulation of protein aggregates in the brain. The direct TH regulation of critical genes involved in amyloid beta production and clearance is remarkable, affecting the expression of multiple genes, including APP (related to amyloid beta production), APOE, LRP1, TREM2, AQP4, and ABCB1 (related to amyloid beta clearance). TH also affects microglia by increasing their migration and function and directly regulating the immunosuppressor gene CD73, impacting the immune response of these cells. Studies aiming to understand the mechanisms that could explain how changes in TH levels can contribute to the brain alterations seen in patients with Alzheimer's are ongoing. These studies have potential implications for the management of patients with Alzheimer's and ultimately can contribute to devising new interventions for these conditions.

An in-silico approach - molecular docking analysis of flavonoids against GSK-3β and TNF-α targets in Alzheimer’s disease

Introduction Drug development for Alzheimer’s disease has one of the greatest failure rates of any therapeutic field and AD is still incurable. Glycogen synthase kinase-3β is a critical enzyme implicated in the pathogenesis of AD, particularly in the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles. TNF-α also plays a significant role in the pathogenesis of Alzheimer’s disease by promoting neuroinflammation, contributing to the formation of amyloid plaques and neurofibrillary tangles, impairing synaptic function, and disrupting the balance of neurotrophic factors. Phytomedicine has numerous advantages over synthetic medications, acting multiple mode of action, including being less toxic and having fewer adverse effects. Flavonoids act as a promising therapeutic target for treating Alzheimer’s disease. The present work investigates the anti-AD potentials of 35 flavonoids for the inhibition of GSK-3β and TNF-α. Methods The physicochemical, pharmacokinetic parameters, toxicity profile and drug-likeliness of the selected 35 flavonoids were predicted using SwissADME & OSIRIS data Warrier property explorer web tool. All flavonoids were selected for docking studies on GSK-3β and TNF-α protein using Autodock 4.2.1. Results The predictions of this study suggested that among the selected 35 flavonoids, Top 3 flavonoids, such as Epicatechin gallate −10.93 kcal/mol, Fisetin −9.44 kcal/mol and Eriodictyol −8.54 kcal/mol for GSK-3β targets. TNF-α Fisetin −11.52 kcal/mol, Sterubin −10.87 kcal/mol, Biochainin A −10.69 kcal/mol were compared with standard drug donepezil. Conclusion Therefore, these flavonoids could be utilized as possible leads for the structure-based design in the advancement of new, strong Anti-Alzheimer’s agents. However, more invitro and invivo analyses are required to finally confirm the outcomes of this research.

Predicting Alzheimer's Cognitive Resilience Score: A Comparative Study of Machine Learning Models Using RNA-seq Data.

Alzheimer's disease (AD) is an important research topic. While amyloid plaques and neurofibrillary tangles are hallmark pathological features of AD, cognitive resilience (CR) is a phenomenon where cognitive function remains preserved despite the presence of these pathological features. This study aimed to construct and compare predictive machine learning models for CR scores using RNA-seq data from the Religious Orders Study and Memory and Aging Project (ROSMAP) and Mount Sinai Brain Bank (MSBB) cohorts. We evaluated support vector regression (SVR), random forest, XGBoost, linear, and transformer-based models. The SVR model exhibited the best performance, with contributing genes identified using Shapley additive explanations (SHAP) scores, providing insights into biological pathways associated with CR. Finally, we developed a tool called the resilience gene analyzer (REGA), which visualizes SHAP scores to interpret the contributions of individual genes to CR. REGA is available at https://igcore.cloud/GerOmics/REsilienceGeneAnalyzer/.

Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus.

Late-onset Alzheimer's disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, including TREM2, ABI3, and CR1. However, GWAS alone cannot pinpoint underlying causal variants or effector genes at such loci, as most signals reside in non-coding regions of the genome and could presumably confer their influence frequently via long-range regulatory interactions. We elected to carry out a combination of ATAC-seq and high-resolution promoter-focused Capture-C in two human microglial cell models (iPSC-derived microglia and HMC3) in order to physically map interactions between LOAD GWAS-implicated candidate causal variants and their corresponding putative effector genes. Notably, we observed consistent evidence that rs6024870 at the GWAS CASS4 locus contacted the promoter of nearby gene, RTFDC1. We subsequently observed a directionallly consistent decrease in RTFDC1 expression with the the protective minor A allele of rs6024870 via both luciferase assays in HMC3 cells and expression studies in primary human microglia. Through CRISPR-Cas9-mediated deletion of the putative regulatory region harboring rs6024870 in HMC3 cells, we observed increased pro-inflammatory cytokine secretion and decreased DNA double strand break repair related, at least in part, to RTFDC1 expression levels. Our variant-to-function approach therefore reveals that the rs6024870-harboring regulatory element at the LOAD 'CASS4' GWAS locus influences both microglial inflammatory capacity and DNA damage resolution, along with cumulative evidence implicating RTFDC1 as a novel candidate effector gene.

Factors associated with cognitive impairment before intracerebral haemorrhage: community-based neuropathological study.

Little is known about whether clinical, radiological or neuropathological features are associated with cognitive impairment before intracerebral haemorrhage. We conducted a community-based cohort study of 125 adults with intracerebral haemorrhage (lobar n = 71, non-lobar n = 54) with consent to brain autopsy. We compared small vessel disease biomarkers on diagnostic CT head and neuropathological findings including neurofibrillary tangles and amyloid plaques in adults without cognitive impairment versus cognitive impairment without dementia versus dementia before intracerebral haemorrhage, stratified by lobar and non-lobar intracerebral haemorrhage. In non-lobar intracerebral haemorrhage, severe cortical atrophy was less common in those without cognitive impairment (8/36, 22%) and cognitive impairment without dementia (0/9, 0%) versus dementia (5/9, 56%); P = 0.008. Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder neurofibrillary tangle pathology measured by median Braak stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [interquartile range, 2-3] versus cognitive impairment without dementia 4 [2-6] versus dementia 5.5 [4-6]; P = 0.004; non-lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [1-2] versus dementia 5 [3-6]; P < 0.001). Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder amyloid plaque pathology measured by median Thal stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [2-3] versus dementia 2.5 [2-3.5]; P = 0.033; non-lobar intracerebral haemorrhage: no cognitive impairment 1 [0-1] versus cognitive impairment without dementia 0 [0-2] versus dementia 3 [2-3]; P = 0.002). Our findings suggest that irrespective of intracerebral haemorrhage location, adults with cognitive impairment before an intracerebral haemorrhage have more Alzheimer's disease neuropathologic change.

Inhibition of Calcineurin with FK506 Reduces Tau Levels and Attenuates Synaptic Impairment Driven by Tau Oligomers in the Hippocampus of Male Mouse Models.

Alzheimer's disease (AD) is the most common age-associated neurodegenerative disorder, characterized by progressive cognitive decline, memory impairment, and structural brain changes, primarily involving Aβ plaques and neurofibrillary tangles of hyperphosphorylated tau protein. Recent research highlights the significance of smaller Aβ and Tau oligomeric aggregates (AβO and TauO, respectively) in synaptic dysfunction and disease progression. Calcineurin (CaN), a key calcium/calmodulin-dependent player in regulating synaptic function in the central nervous system (CNS) is implicated in mediating detrimental effects of AβO on synapses and memory function in AD. This study aims to investigate the specific impact of CaN on both exogenous and endogenous TauO through the acute and chronic inhibition of CaN. We previously demonstrated the protective effect against AD of the immunosuppressant CaN inhibitor, FK506, but its influence on TauO remains unclear. In this study, we explored the short-term effects of acute CaN inhibition on TauO phosphorylation and TauO-induced memory deficits and synaptic dysfunction. Mice received FK506 post-TauO intracerebroventricular injection and TauO levels and phosphorylation were assessed, examining their impact on CaN and GSK-3β. The study investigated FK506 preventive/reversal effects on TauO-induced clustering of CaN and GSK-3β. Memory and synaptic function in TauO-injected mice were evaluated with/without FK506. Chronic FK506 treatment in 3xTgAD mice explored its influence on CaN, Aβ, and Tau levels. This study underscores the significant influence of CaN inhibition on TauO and associated AD pathology, suggesting therapeutic potential in targeting CaN for addressing various aspects of AD onset and progression. These findings provide valuable insights for potential interventions in AD, emphasizing the need for further exploration of CaN-targeted strategies.

Amyloid-β Pathology Is the Common Nominator Proteinopathy of the Primate Brain Aging.

Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging.

A multi-targeting immunotherapy ameliorates multiple facets of Alzheimer’s disease in 3xTg mice

Alzheimer’s disease (AD) is an intricate disorder involving amyloid deposits, neurofibrillary tangles, and chronic neuroinflammation. Though current Aβ-directed immunotherapies effectively eliminate amyloid plaques, their limited clinical benefits and notable safety concerns arise from overlooking two other neglected neurodegenerative features. Compelling evidence highlights synergistic cooperation between Aβ and tau, underscoring the imperative need to develop combinational therapies to target the diverse pathologies of AD. In this study, we present a dual AD vaccine combining Aβ and pTau vaccines, eliciting robust and enduring antibody responses against pathological Aβ and pTau in 3xTg transgenic mice. It significantly eradicated Aβ plaques and pTau tangles, suppressed neuroinflammatory factors, and markedly enhancing cognitive abilities in 3xTg mice. Mechanistically, peripheral antibodies penetrated the brain, recognizing and inhibiting Aβ and pTau aggregation, thereby reducing their cytotoxicity. In summary, this innovative multi-targeting immunotherapy remarkably ameliorates diverse AD pathologies, demonstrating maximum benefits in slowing the clinical progression of AD.

Dendrimers-Novel Therapeutic Approaches for Alzheimer's Disease.

Dendrimers are covalently bonded globular nanostructures that may be used in the treatment of Alzheimer's disease (AD). Nowadays, AD therapies are focused on improving cognitive functioning and not causal treatment. However, this may change with the use of dendrimers, which are being investigated as a drug-delivery system or as a drug per se. With their ability to inhibit amyloid formation and their anti-tau properties, they are a promising therapeutic option for AD patients. Studies have shown that dendrimers may inhibit amyloid formation in at least two ways: by blocking fibril growth and by breaking already existing fibrils. Neurofibrillary tangles (NFTs) are abnormal filaments built by tau proteins that can be accumulated in the cell, which leads to the loss of cytoskeletal microtubules and tubulin-associated proteins. Cationic phosphorus dendrimers, with their anti-tau properties, can induce the aggregation of tau into amorphous structures. Drug delivery to mitochondria is difficult due to poor transport across biological barriers, such as the inner mitochondrial membrane, which is highly negatively polarized. Dendrimers may be potential nanocarriers and increase mitochondria targeting. Another considered use of dendrimers in AD treatment is as a drug-delivery system, for example, carbamazepine (CBZ) or tacrine. They can also be used to transport siRNA into neuronal tissue and to carry antioxidants and anti-inflammatory drugs to act protectively on the nervous system.

Influence of Exercise and Genistein to Mitigate the Deleterious Effects of High-Fat High-Sugar Diet on Alzheimer's Disease-Related Markers in Male Mice.

The prevalence of obesity and related consequences, including insulin resistance and Alzheimer's-like neuropathology, has increased dramatically. Contributing to this prevalence is the shift in lifestyle preference away from wholesome foods and exercise to the Western-style diet and sedentarism. Despite advances in drug development, a healthy diet and regular exercise remain the most effective approaches to mitigating the unwanted sequelae of diet-induced obesity on brain health. In this study, we used the high-fat high-sugar (HFHS) mouse model of neurodegeneration to examine the effects of exercise training (HFHS+Ex), genistein treatment (HFHS+Gen), and combination treatment (HFHS+Ex+Gen) on proteins relating to neurodegeneration in the brain of male mice. After a period of 12 weeks, as expected, HFHS feeding increased body weight, adipose tissue weight, and systemic plasma inflammation (TNF-α) compared to lean mice fed a standard diet. HFHS feeding also increased protein expression of brain markers of insulin resistance (pGSK-3β, p-IR), apoptosis (caspase 3), early neurofibrillary tangles (CP13), and amyloid-beta precursor (CT20). Compared to HFHS mice, Ex decreased body weight, plasma TNF-α, and expression of pGSK-3β, caspase 3, CP13, amyloid-β precursor (22c11), and ADAM10. Treatment with Gen was equally protective on these markers and decreased the expression of p-IR. Combination treatment with Ex and Gen afforded the greatest overall benefits, and this group exhibited the greatest reduction in body and adipose tissue weight and all brain markers, except for 22c11 and ADAM10, which were decreased compared to mice fed an HFHS diet. In addition, levels of 4G8, which detects protein levels of amyloid-β, were decreased with combination treatment. Our results indicate that exercise training, genistein supplementation, or combination treatment provide varying degrees of neuroprotection from HFHS feeding-induced Alzheimer's pathology. Future perspectives could include evaluating moderate exercise regimens in combination with dietary supplementation with genistein in humans to determine whether the same benefits translate clinically.

Iron Chelators and Alzheimer's Disease Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-β (Aβ) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aβ plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research.

Improving Cognition Without Clearing Amyloid: Effects of Tau and Ultrasound Neuromodulation.

Alzheimer's disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature of dementia is protein aggregation, a process by which a monomer forms intermediate oligomeric assembly states and filaments that develop into end-stage hallmark lesions. In Alzheimer's disease, this is exemplified by extracellular amyloid-β (Aβ) plaques which have been placed upstream of tau, found in intracellular neurofibrillary tangles and dystrophic neurites. This implies causality that can be modeled as a linear activation cascade. When Aβ load is reduced, for example, in response to an anti-Aβ immunotherapy, cognitive functions improve in plaque-forming mice. They also deteriorate less in clinical trial cohorts although real-world clinical benefits remain to be demonstrated. Given the existence of aged humans with unimpaired cognition despite a high plaque load, the central role of Aβ has been challenged. A counter argument has been that clinical symptoms would eventually develop if these aged individuals were to live long enough. Alternatively, intrinsic mechanisms that protect the brain in the presence of pathology may exist. In fact, Aβ toxicity can be abolished by either reducing or manipulating tau (through which Aβ signals), at least in preclinical models. In addition to manipulating steps in this linear pathocascade model, mechanisms of restoring brain reserve can also counteract Aβ toxicity. Low-intensity ultrasound is a neuromodulatory modality that can improve cognitive functions in Aβ-depositing mice without the need for removing Aβ. Together, this highlights a dissociation of Aβ and cognition, with important implications for therapeutic interventions.

Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases

The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer’s disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer’s disease (n = 17), primary tauopathies (n = 8), synucleinopathies (n = 27), frontotemporal lobar degeneration (n = 8), mixed pathology (n = 11), other neurodegenerative diseases (n = 6), and cognitively normal controls (n = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer’s disease, primary tauopathies and controls with Alzheimer’s disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (n = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (n = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (n = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (n = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates associated with the main neurodegenerative disease. These findings indicate that with appropriate retinal imaging techniques, retinal biomarkers have the potential to become highly accurate indicators for diagnosing the major neurodegenerative diseases of the brain.

Associations between Brain Alpha-Tocopherol Stereoisomer Profile and Hallmarks of Brain Aging in Centenarians.

Brain alpha-tocopherol (αT) concentration was previously reported to be inversely associated with neurofibrillary tangle (NFT) counts in specific brain structures from centenarians. However, the contribution of natural or synthetic αT stereoisomers to this relationship is unknown. In this study, αT stereoisomers were quantified in the temporal cortex (TC) of 47 centenarians in the Georgia Centenarian Study (age: 102.2 ± 2.5 years, BMI: 22.1 ± 3.9 kg/m2) and then correlated with amyloid plaques (diffuse and neuritic plaques; DPs, NPs) and NFTs in seven brain regions. The natural stereoisomer, RRR-αT, was the primary stereoisomer in all subjects, accounting for >50% of total αT in all but five subjects. %RRR was inversely correlated with DPs in the frontal cortex (FC) (ρ = -0.35, p = 0.032) and TC (ρ = -0.34, p = 0.038). %RSS (a synthetic αT stereoisomer) was positively correlated with DPs in the TC (ρ = 0.39, p = 0.017) and with NFTs in the FC (ρ = 0.37, p = 0.024), TC (ρ = 0.42, p = 0.009), and amygdala (ρ = 0.43, p = 0.008) after controlling for covariates. Neither RRR- nor RSS-αT were associated with premortem global cognition. Even with the narrow and normal range of BMIs, BMI was correlated with %RRR-αT (ρ = 0.34, p = 0.021) and %RSS-αT (ρ = -0.45, p = 0.002). These results providing the first characterization of TC αT stereoisomer profiles in centenarians suggest that DP and NFT counts, but not premortem global cognition, are influenced by the brain accumulation of specific αT stereoisomers. Further study is needed to confirm these findings and to determine the potential role of BMI in mediating this relationship.

Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.

Relationships between regional burden of tau pathology and age at death and disease duration in PSP

BackgroundA definitive diagnosis of progressive supranuclear palsy (PSP) can only be established through neuropathological evaluations where four cardinal tau lesions are identified. Relationships between regional tau burden and disease duration/age at death is unclear. ObjectiveTo investigate relationships between tau burden in different brain regions and disease duration and age at death in PSP and determine whether association are influenced by PSP subtype (subcortical/cortical) or co-pathologies. MethodsWe identified 45 patients with definite PSP who were evaluated at Mayo Clinic between 2009 and 2023, died and underwent histopathological evaluation. We performed semi-quantitative lesion count for each of four cardinal lesions (pretangles/globose neurofibrillary tangles, threads, tufted astrocytes, and coiled bodies) across 10 brain regions. We fit Bayesian linear hierarchical regression models to estimate the relationship between total pathological burden, and disease duration and age at death by region and the influence of subtype and co-pathologies. ResultsOf the 45 patients, 18 (40 %) were female. Median age at death was 75 (56–87) years and median disease duration was 8 (3,15) years. Younger age at death was associated with greater total tau burden in the pallidum, red nucleus, striatum, and subthalamic nucleus (all p ≤ 0.01). Shorter disease duration was associated with greater total tau burden in the red nucleus (p = 0.05). There was no evidence for a difference in association between lesion types. PSP subtype and co-pathologies did not influence associations. ConclusionsThe findings from this study suggest that age and disease duration influence burden of tau pathology in subcortical regions in PSP.

Loss of DNA glycosylases improves health and cognitive function in a C. elegans model of human tauopathy.

Alzheimer's disease (AD) is a neurodegenerative disorder representing a major burden on families and society. Some of the main pathological hallmarks of AD are the accumulation of amyloid plaques (Aβ) and tau neurofibrillary tangles. However, it is still unclear how Aβ and tau aggregates promote specific phenotypic outcomes and lead to excessive oxidative DNA damage, neuronal cell death and eventually to loss of memory. Here we utilized a Caenorhabditis elegans (C. elegans)model of human tauopathy to investigate the role of DNA glycosylases in disease development and progression. Transgenic nematodes expressing a pro-aggregate form of tau displayed altered mitochondrial content, decreased lifespan, and cognitive dysfunction. Genetic ablation of either of the two DNA glycosylases found in C. elegans, NTH-1 and UNG-1, improved mitochondrial function, lifespan, and memory impairment. NTH-1 depletion resulted in a dramatic increase of differentially expressed genes, which was not apparent in UNG-1 deficient nematodes. Our findings clearly show that in addition to its enzymatic activity, NTH-1 has non-canonical functions highlighting its modulation as a potential therapeutic intervention to tackle tau-mediated pathology.

Astrocytic centrin-2 expression in entorhinal cortex correlates with Alzheimer's disease severity.

Astrogliosis is a condition shared by acute and chronic neurological diseases and includes morphological, proteomic, and functional rearrangements of astroglia. In Alzheimer's disease (AD), reactive astrocytes frame amyloid deposits and exhibit structural changes associated with the overexpression of specific proteins, mostly belonging to intermediate filaments. At a functional level, amyloid beta triggers dysfunctional calcium signaling in astrocytes, which contributes to the maintenance of chronic neuroinflammation. Therefore, the identification of intracellular players that participate in astrocyte calcium signaling can help unveil the mechanisms underlying astrocyte reactivity and loss of function in AD. We have recently identified the calcium-binding protein centrin-2 (CETN2) as a novel astrocyte marker in the human brain and, in order to determine whether astrocytic CETN2 expression and distribution could be affected by neurodegenerative conditions, we examined its pattern in control and sporadic AD patients. By immunoblot, immunohistochemistry, and targeted-mass spectrometry, we report a positive correlation between entorhinal CETN2 immunoreactivity and neurocognitive impairment, along with the abundance of amyloid depositions and neurofibrillary tangles, thus highlighting a linear relationship between CETN2 expression and AD progression. CETN2-positive astrocytes were dispersed in the entorhinal cortex with a clustered pattern and colocalized with reactive glia markers STAT3, NFATc3, and YKL-40, indicating a human-specific role in AD-induced astrogliosis. Collectively, our data provide the first evidence that CETN2 is part of the astrocytic calcium toolkit undergoing rearrangements in AD and adds CETN2 to the list of proteins that could play a role in disease evolution.