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Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease 1 , 2 . The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition 3 – 5 , and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology 6 . Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies. A study finds T cells in areas of tau, not amyloid, pathology in Alzheimer’s disease brain and mouse models, with their presence correlating with neuronal loss and their depletion, or that of microglia, preventing neurodegeneration and cognitive decline.

Alzheimer’s disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline 1 . The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity 2 , 3 . We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with ‘typical’ AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD. A molecular analysis of tau from patients with sporadic Alzheimer’s disease reveals striking diversity in biochemical properties between patients, which influences seeding activity and correlates with the aggressiveness of the disease.

Alzheimer’s disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H₂S) is dysregulated during aging. H₂S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H₂S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H₂S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3β (GSK3β). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention 1 , 2 . However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297–391) into paired helical filaments of Alzheimer’s disease or into filaments of chronic traumatic encephalopathy 3 . We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302–316. Nuclear magnetic resonance indicates that the same residues adopt rigid, β-strand-like conformations in monomeric tau. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of new therapies. A time-resolved cryogenic electron microscopy analysis provides structural information on the processes of primary and secondary nucleation of tau amyloid formation, with implications for the development of new therapies.

The key pathological hallmarks—extracellular plaques and intracellular neurofibrillary tangles (NFT)—described by Alois Alzheimer in his seminal 1907 article are still central to the postmortem diagnosis of Alzheimer's disease (AD), but major advances in our understanding of the underlying pathophysiology as well as significant progress in clinical diagnosis and therapy have changed the perspective and importance of neuropathologic evaluation of the brain. The notion that the pathological processes underlying AD already start decades before symptoms are apparent in patients has brought a major change reflected in the current neuropathological classification of AD neuropathological changes (ADNC). The predictable progression of beta-amyloid (Aβ) plaque pathology from neocortex, over limbic structures, diencephalon, and basal ganglia, to brainstem and cerebellum is captured in phases described by Thal and colleagues. The progression of NFT pathology from the transentorhinal region to the limbic system and ultimately the neocortex is described in stages proposed by Braak and colleagues. The density of neuritic plaque pathology is determined by criteria defined by the Consortium to establish a registry for Alzheimer's diseases (CERAD). While these changes neuropathologically define AD, it becomes more and more apparent that the majority of patients present with a multitude of additional pathological changes which are possible contributing factors to the clinical presentation and disease progression. The impact of co-existing Lewy body pathology has been well studied, but the importance of more recently described pathologies including limbic-predominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy (ARTAG) still needs to be evaluated in large cohort studies. In addition, it is apparent that vascular pathology plays an important role in the AD patient population, but a lack of standardized reporting criteria has hampered progress in elucidating the importance of these changes for clinical presentation and disease progression. More recently a key role was ascribed to the immune response to pathological protein aggregates, and it will be important to analyze these changes systematically to better understand the temporal and spatial distribution of the immune response in AD and elucidate their importance for the disease process. Advances in digital pathology and technologies such as single cell sequencing and digital spatial profiling have opened novel avenues for improvement of neuropathological diagnosis and advancing our understanding of underlying molecular processes. Finally, major strides in biomarker-based diagnosis of AD and recent advances in targeted therapeutic approaches may have shifted the perspective but also highlight the continuous importance of postmortem analysis of the brain in neurodegenerative diseases.

Microscopic imaging of neurons in mouse models of Alzheimer’s disease shows that plaques increase activity while neurofibrillary tangles suppress activity. The combination of plaques and tangles, as in humans with Alzheimer’s disease, suppresses activity.

Alzheimer’s disease (AD) is the foremost type of dementia that afflicts considerable morbidity and mortality in aged population. Several transcription molecules, pathways, and molecular mechanisms such as oxidative stress, inflammation, autophagy, and immune system interact in a multifaceted way that disrupt physiological processes (cell growth, differentiation, survival, lipid and energy metabolism, endocytosis) leading to apoptosis, tauopathy, β -amyloidopathy, neuron, and synapse loss, which play an important role in AD pathophysiology. Despite of stupendous advancements in pathogenic mechanisms, treatment of AD is still a nightmare in the field of medicine. There is compelling urgency to find not only symptomatic but effective disease-modifying therapies. Recently, phosphoinositide 3-kinase (PI3K) and Akt are identified as a pathway triggered by diverse stimuli, including insulin, growth factors, cytokines, and cellular stress, that link amyloid- β , neurofibrillary tangles, and brain atrophy. The present review aims to explore and analyze the role of PI3K-Akt pathway in AD and agents which may modulate Akt and have therapeutic prospects in AD. The literature was researched using keywords “PI3K-Akt” and “Alzheimer’s disease” from PubMed, Web of Science, Bentham, Science Direct, Springer Nature, Scopus, and Google Scholar databases including books. Articles published from 1992 to 2021 were prioritized and analyzed for their strengths and limitations, and most appropriate ones were selected for the purpose of review. PI3K-Akt pathway regulates various biological processes such as cell proliferation, motility, growth, survival, and metabolic functions, and inhibits many neurotoxic mechanisms. Furthermore, experimental data indicate that PI3K-Akt signaling might be an important therapeutic target in treatment of AD.

Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer’s disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts ( n  = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding ( β  = 0.72, R 2  = 0.56) and cognitive performance ( β  = 0.60, R 2  = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials. Plasma eMTBR-tau243 is a specific biomarker of tau tangles in Alzheimer’s disease and enables the detecting and tracking of Alzheimer’s clinical impairment.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n  = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN–/SOX10– (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in ‘bulk’ cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types. Here the authors identify differences in cortical DNA methylation associated with Alzheimer’s disease pathology, and profiling nuclei from specific cell-types, find that most of these differences reflect variation occurring in non-neuronal cells.