Misfolded Tau Protein Research Articles

Arc mediates intercellular tau transmission via extracellular vesicles.

Intracellular neurofibrillary tangles that consist of misfolded tau protein 1 cause neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Tau pathology spreads cell-to-cell 2 but the exact mechanisms of tau release and intercellular transmission remain poorly defined. Tau is released from neurons as free protein or in extracellular vesicles (EVs) 3-5 but the role of these different release mechanisms in intercellular tau transmission is unclear. Here, we show that the neuronal gene Arc is critical for packaging tau into EVs. Brain EVs purified from human tau (hTau) transgenic rTg4510 mice (rTg WT ) contain high levels of hTau that are capable of seeding tau pathology. In contrast, EVs purified from rTg WT crossed with Arc knock-out mice (rTg Arc KO ) have significantly less hTau and cannot seed tau aggregation. Arc facilitates the release of hTau in EVs produced via the I-BAR protein IRSp53, but not free tau. Arc protein directly binds hTau to form a fuzzy complex that we identified in both mouse and human brain tissue. We find that pathological intracellular hTau accumulates in neurons in rTg Arc KO mice, which correlates with accelerated neuron loss in the hippocampus. Finally, we find that intercellular tau transmission is significantly abrogated in Arc KO mice. We conclude that Arc-dependent release of tau in EVs plays a significant role in intracellular tau elimination and intercellular tau transmission.

Advances in Understanding and Managing Alzheimer's Disease: From Pathophysiology to Innovative Therapeutic Strategies.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the presence of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles, leading to cognitive and physical decline. Representing the majority of dementia cases, AD poses a significant burden on healthcare systems globally, with onset typically occurring after the age of 65. While most cases are sporadic, about 10% exhibit autosomal forms associated with specific gene mutations. Neurofibrillary tangles and Aβ plaques formed by misfolded tau proteins and Aβ peptides contribute to neuronal damage and cognitive impairment. Currently, approved drugs, such as acetylcholinesterase inhibitors and N-methyl D-aspartate receptor agonists, offer only partial symptomatic relief without altering disease progression. A promising development is using lecanemab, a humanized IgG1 monoclonal antibody, as an immune therapeutic approach. Lecanemab demonstrates selectivity for polymorphic Aβ variants and binds to large soluble Aβ aggregates, providing a potential avenue for targeted treatment. This shift in understanding the role of the adaptive immune response in AD pathogenesis opens new possibilities for therapeutic interventions aiming to address the disease's intricate mechanisms. This review aims to summarize recent advancements in understanding Alzheimer's disease pathophysiology and innovative therapeutic approaches, providing valuable insights for both researchers and clinicians.

Disruption in functional networks mediated tau spreading in Alzheimer's disease.

Alzheimer's disease may be conceptualized as a 'disconnection syndrome', characterized by the breakdown of neural connectivity within the brain as a result of amyloid-beta plaques, tau neurofibrillary tangles and other factors leading to progressive degeneration and shrinkage of neurons, along with synaptic dysfunction. It has been suggested that misfolded tau proteins spread through functional connections (known as 'prion-like' properties of tau). However, the local effect of tau spreading on the synaptic function and communication between regions is not well understood. I aimed to investigate how the spreading of tau aggregates through connections can locally influence functional connectivity. In total, the imaging data of 211 participants including 117 amyloid-beta-negative non-demented and 94 amyloid-beta-positive non-demented participants were recruited from the Alzheimer's Disease Neuroimaging Initiative. Furthermore, normative resting-state functional MRI connectomes were used to model tau spreading through functional connections, and functional MRI of the included participants was used to determine the effect of tau spreading on functional connectivity. I found that lower functional connectivity to tau epicentres is associated with tau spreading through functional connections in both amyloid-beta-negative and amyloid-beta-positive participants. Also, amyloid-beta-PET in tau epicentres mediated the association of tau spreading and functional connectivity to epicentres suggesting a partial mediating effect of amyloid-beta deposition in tau epicentres on the local effect of tau spreading on functional connectivity. My findings provide strong support for the notion that tau spreading through connection is locally associated with disrupted functional connectivity between tau epicentre and non-epicentre regions independent of amyloid-beta pathology. Also, I defined several groups based on the relationship between tau spreading and functional disconnection, which provides quantitative assessment to investigate susceptibility or resilience to functional disconnection related to tau spreading. I showed that amyloid-beta, other copathologies and the apolipoprotein E epsilon 4 allele can be a leading factor towards vulnerability to tau relative functional disconnection.

The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges.

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease and over twenty neurodegenerative disorders. However, the molecular mechanisms of tau aggregation in vivo remain incompletely understood. There are two types of tau aggregates in the brain: soluble aggregates (oligomers and protofibrils) and insoluble filaments (fibrils). Compared to filamentous aggregates, soluble aggregates are more toxic and exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, in its native state, tau is a highly soluble, heat-stable protein that does not form fibrils by itself, not even when hyperphosphorylated. In vitro studies have found that negatively charged molecules such as heparin, RNA, or arachidonic acid are generally required to induce tau aggregation. Two recent breakthroughs have provided new insights into tau aggregation mechanisms. First, as an intrinsically disordered protein, tau is found to undergo liquid-liquid phase separation (LLPS) both in vitro and inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar tau conformations associated with different neurodegenerative disorders. Nonetheless, only the fibrillar core is structurally resolved, and the remainder of the protein appears as a "fuzzy coat". From this review, it appears that further studies are required (1) to clarify the role of LLPS in tau aggregation; (2) to unveil the structural features of soluble tau aggregates; (3) to understand the involvement of fuzzy coat regions in oligomer and fibril formation.

Neurophysiological trajectories in Alzheimer's disease progression.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

Neurophysiological trajectories in Alzheimer’s disease progression

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

Neuropathology, Neuroimaging, and Fluid Biomarkers in Alzheimer's Disease.

An improved understanding of the pathobiology of Alzheimer's disease (AD) should lead ultimately to an earlier and more accurate diagnosis of AD, providing the opportunity to intervene earlier in the disease process and to improve outcomes. The known hallmarks of Alzheimer's disease include amyloid-β plaques and neurofibrillary tau tangles. It is now clear that an imbalance between production and clearance of the amyloid beta protein and related Aβ peptides, especially Aβ42, is a very early, initiating factor in Alzheimer's disease (AD) pathogenesis, leading to aggregates of hyperphosphorylation and misfolded tau protein, inflammation, and neurodegeneration. In this article, we review how the AD diagnostic process has been transformed in recent decades by our ability to measure these various elements of the pathological cascade through the use of imaging and fluid biomarkers. The more recently developed plasma biomarkers, especially phosphorylated-tau217 (p-tau217), have utility for screening and diagnosis of the earliest stages of AD. These biomarkers can also be used to measure target engagement by disease-modifying therapies and the response to treatment.

Combining multimodal connectivity information improves modelling of pathology spread in Alzheimer's disease.

Cortical atrophy and aggregates of misfolded tau proteins are key hallmarks of Alzheimer's disease. Computational models that simulate the propagation of pathogens between connected brain regions have been used to elucidate mechanistic information about the spread of these disease biomarkers, such as disease epicentres and spreading rates. However, the connectomes that are used as substrates for these models are known to contain modality-specific false positive and false negative connections, influenced by the biases inherent to the different methods for estimating connections in the brain. In this work, we compare five types of connectomes for modelling both tau and atrophy patterns with the network diffusion model, which are validated against tau PET and structural MRI data from individuals with either mild cognitive impairment or dementia. We then test the hypothesis that a joint connectome, with combined information from different modalities, provides an improved substrate for the model. We find that a combination of multimodal information helps the model to capture observed patterns of tau deposition and atrophy better than any single modality. This is validated with data from independent datasets. Overall, our findings suggest that combining connectivity measures into a single connectome can mitigate some of the biases inherent to each modality and facilitate more accurate models of pathology spread, thus aiding our ability to understand disease mechanisms, and providing insight into the complementary information contained in different measures of brain connectivity.

Mechanisms linking cerebrovascular dysfunction and tauopathy: Adding a layer of epiregulatory complexity.

Intracellular accumulation of hyperphosphorylated misfolded tau proteins are found in many neurodegenerative tauopathies, including Alzheimer's disease (AD). Tau pathology can impact cerebrovascular physiology and function through multiple mechanisms. In vitro and in vivo studies have shown that alterations in the blood-brain barrier (BBB) integrity and function can result in synaptic abnormalities and neuronal damage. In the present review, we will summarize how tau proteostasis dysregulation contributes to vascular dysfunction and, conversely, we will examine the factors and pathways leading to tau pathological alterations triggered by cerebrovascular dysfunction. Finally, we will highlight the role epigenetic and epitranscriptomic factors play in regulating the integrity of the cerebrovascular system and the progression of tauopathy including a few observartions on potential therapeutic interventions. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Early locus coeruleus degeneration impairs the longevity of fear memory in APPswe/PS1dE9 mice

AbstractBackgroundThe locus coeruleus (LC), a brainstem noradrenergic nucleus is known to modulate cognitive functions and behaviour. LC is one the first sites of appearance of misfolded tau protein which later develops into neurofibrillary tangles. Hyperphosphorylated tau and amyloid β are best protein correlates of cognitive decline in Alzheimer’s disease (AD). In early onset AD, subtle cognitive deficits develop <25 years before the patients develop dementia. Loss of LC neurons and its innervation has been found to be significantly associated with behavioural deficits observed during prodromal stage of AD. However, the extent and consequences of LC‐noradrenergic system degeneration during early stages of AD pathogenesis are still under investigation.MethodTo address this question, we have performed contextual fear conditioning (cFC) behavioural task to test fear memory in 2‐month‐old APPswe/PS1dE9 (APP/PS1) mice, a transgenic amyloidogenic model of AD. We further investigated the status of LC terminals and the distribution of β‐adrenoceptors (β‐AR) in the hippocampus using dopamine‐β‐hydroxylase (DBH), tyrosine hydroxylase (TH), and β‐AR immunohistochemistry respectively. Finally, we checked if stereotaxic delivery of β‐AR agonist to the hippocampus could rescue the impairments in long‐term fear memory.ResultOur study demonstrates that 2‐month‐old male but not female APP/PS1 mice exhibit impaired long‐term fear memory in cFC task. Immunohistochemical analysis of DBH and TH positive nerve terminals revealed loss of noradrenergic and dopaminergic terminals in male but not female APP/PS1 mice hippocampus. Further, male APP/PS1 mice were found to have low levels of β‐AR in the hippocampus and intra‐hippocampal administration of isoproterenol hydrochloride, a β‐AR agonist, immediately before cFC could restore long‐term contextual fear memory.ConclusionLC‐noradrenergic system degeneration displayed an inherent sex‐specific difference on longevity of fear memory with deficits occurring only in male APP/PS1 mice during early stages of AD.

To Assess Mediation Effects of BIN1 Risk Variant rs6733839 and APOE4 on Alzheimer’s disease Pathology

AbstractBackgroundAlzheimer’s disease (AD) patients carrying T‐allele in the single nucleotide polymorphism rs744373 show higher levels of misfolded tau protein levels, as well as faster accumulation of neurofibrillary tangles (Franzmeier‐2019; Franzmeier‐2022), in addition to established risk gene apolipoprotein E (APOE4). Here we conduct pathway analysis to understand the direct and indirect effects, mediated through amyloid levels, of the rs6733839 T‐allele and APOE e4‐allele on tau.MethodAmyloid‐positive (florbetapir PET) placebo‐arm patients with a clinical diagnosis of AD dementia from four clinical trials (NCT01900665, NCT02791191, NCT02245737, NCT02016560, Table.1) underwent baseline (N = 547) and follow‐up (N = 230) flortaucipir PET scans. Tau burden was assessed using standardized uptake value ratio (SUVr) in AD‐specific region (MUBADA; Devous‐2018) with respect to cerebellum‐crus. We tested direct and indirect effects of BIN1 (rs6733839) and APOE4 on baseline SUVr and change‐from baseline (CFB) in tau‐PET mediated by baseline florbetapir signal. Unstandardized indirect effects were computed for each of 1,000 bootstrapped samples, and the 95% confidence interval was computed by determining the indirect effects at the 2.5th and 97.5th percentiles.ResultBIN1 and age showed significant association with the baseline tau‐PET level (BIN1: ßeta = 0.05, P = 0.05; Age: ßeta = ‐0.03, P<0.001), whereas APOE4 association with the baseline tau‐PET levels was not statistically significant (ßeta = 0.006, P = 0.81). The bootstrapped unstandardized indirect effect of BIN1, age, and APOE4 mediated via baseline amyloid levels was insignificant (BIN1: ßeta = 0.0002, P = 0.92; Age: ßeta = 3.82e−05, P = 0.74; APOE4: ßeta = ‐0.0003, P = 0.86). When evaluated on longitudinal tau measures, the direct effect of APOE4 on CFB in tau‐PET SUVr was significant (ßeta = 0.02; P = 0.01). The direct and indirect effects (mediated via baseline amyloid levels) of BIN1 (Direct: ßeta = ‐0.007, P = 0.215; Indirect: ßeta = ‐0.0007, P = 0.58) and Age (Direct: ßeta = ‐0.0009, P = 0.26; Indirect: ßeta = 0.0001, P = 0.32) were insignificant.ConclusionBIN1 showed significant association with the baseline tau‐PET level whereas APOE‐e4 allele directly affected longitudinal tau buildup independent of amyloid levels. These observations require additional validation using larger datasets and further optimization of the applied methodology is warranted.

Discovering a reaction–diffusion model for Alzheimer’s disease by combining PINNs with symbolic regression

Misfolded tau proteins play a critical role in the progression and pathology of Alzheimer’s disease. Recent studies suggest that the spatio-temporal pattern of misfolded tau follows a reaction–diffusion type equation. However, the precise mathematical model and parameters that characterize the progression of misfolded protein across the brain remain incompletely understood. Here, we use deep learning and artificial intelligence to discover a mathematical model for the progression of Alzheimer’s disease using longitudinal tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative database. Specifically, we integrate physics informed neural networks (PINNs) and symbolic regression to discover a reaction–diffusion type partial differential equation for tau protein misfolding and spreading. First, we demonstrate the potential of our model and parameter discovery on synthetic data. Then, we apply our method to discover the best model and parameters to explain tau imaging data from 46 individuals who are likely to develop Alzheimer’s disease and 30 healthy controls. Our symbolic regression discovers different misfolding models f(c) for two groups, with a faster misfolding for the Alzheimer’s group, f(c)=0.23c3−1.34c2+1.11c, than for the healthy control group, f(c)=−c3+0.62c2+0.39c. Our results suggest that PINNs, supplemented by symbolic regression, can discover a reaction–diffusion type model to explain misfolded tau protein concentrations in Alzheimer’s disease. We expect our study to be the starting point for a more holistic analysis to provide image-based technologies for early diagnosis, and ideally early treatment of neurodegeneration in Alzheimer’s disease and possibly other misfolding-protein based neurodegenerative disorders.

Spreading of Tau Protein Does Not Depend on Aggregation Propensity

The stereotypical progression of Tau pathology during Alzheimer disease has been attributed to trans-neuronal spreading of misfolded Tau proteins, followed by prion-like templated aggregation of Tau. The nature of Tau and the cellular mechanisms of Tau spreading are still under debate. We hypothesized that Tau’s propensity for aggregation would correlate with its ability to spread across synapses and propagate pathology. To study the progressive propagation of Tau proteins in brain regions relevant for Alzheimer disease, we used mice expressing near-physiological levels of full-length human Tau protein carrying pro-aggregant (TauΔK280, TauΔK) or anti-aggregant (TauΔK280-PP, TauΔK−PP) mutations in the entorhinal cortex (EC). To enhance Tau expression in the EC, we performed EC injections of adeno-associated virus (AAV) particles encoding TauΔK or TauΔK−PP. The brains of injected and non-injected EC/TauΔK and EC/TauΔK−PP mice were studied by immunohistological and biochemical techniques to detect Tau propagation to dentate gyrus (DG) neurons and Tau-induced pathological changes. Pro- and anti-aggregant mice had comparable low transgene expression (~0.2 times endogenous mouse Tau). They accumulated human Tau at similar rates and only in expressing EC neurons, including their axonal projections of the perforant path and presynaptic terminals in the molecular layer of the DG. Pro-aggregant EC/TauΔK mice showed misfolded Tau and synaptic protein alterations in EC neurons, not observed in anti-aggregant EC/TauΔK−PP mice. Additional AAV-mediated expression of TauΔK or TauΔK−PP in EC/TauΔK or EC/TauΔK−PP mice, respectively, increased the human Tau expression to ~0.65 times endogenous mouse Tau, with comparable spreading of TauΔK and TauΔK−PP throughout the EC. There was a low level of transcellular propagation of Tau protein, without pathological phosphorylation or misfolding, as judged by diagnostic antibodies. Additionally, TauΔK but not TauΔK−PP expression induced hippocampal astrogliosis. Low levels of pro- or anti-aggregant full-length Tau show equivalent distributions in EC neurons, independent of their aggregation propensity. Increasing the expression via AAV induce local Tau misfolding in the EC neurons, synaptotoxicity, and astrogliosis and lead to a low level of detectable trans-neuronal spreading of Tau. This depends on its concentration in the EC, but, contrary to expectations, does not depend on Tau’s aggregation propensity/misfolding and does not lead to templated misfolding in recipient neurons.

Revisiting the neuroinflammation hypothesis in Alzheimer's disease: a focus on the druggability of current targets.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease and disability in the elderly; it is estimated to account for 60%-70% of all cases of dementia worldwide. The most relevant mechanistic hypothesis to explain AD symptoms is neurotoxicity induced by aggregated amyloid-β peptide (Aβ) and misfolded tau protein. These molecular entities are seemingly insufficient to explain AD as a multifactorial disease characterized by synaptic dysfunction, cognitive decline, psychotic symptoms, chronic inflammatory environment within the central nervous system (CNS), activated microglial cells, and dysfunctional gut microbiota. The discovery that AD is a neuroinflammatory disease linked to innate immunity phenomena started in the early nineties by several authors, including the ICC´s group that described, in 2004, the role IL-6 in AD-type phosphorylation of tau protein in deregulating the cdk5/p35 pathway. The "Theory of Neuroimmunomodulation", published in 2008, proposed the onset and progression of degenerative diseases as a multi-component "damage signals" phenomena, suggesting the feasibility of "multitarget" therapies in AD. This theory explains in detail the cascade of molecular events stemming from microglial disorder through the overactivation of the Cdk5/p35 pathway. All these knowledge have led to the rational search for inflammatory druggable targets against AD. The accumulated evidence on increased levels of inflammatory markers in the cerebrospinal fluid (CSF) of AD patients, along with reports describing CNS alterations caused by senescent immune cells in neuro-degenerative diseases, set out a conceptual framework in which the neuroinflammation hypothesis is being challenged from different angles towards developing new therapies against AD. The current evidence points to controversial findings in the search for therapeutic candidates to treat neuroinflammation in AD. In this article, we discuss a neuroimmune-modulatory perspective for pharmacological exploration of molecular targets against AD, as well as potential deleterious effects of modifying neuroinflammation in the brain parenchyma. We specifically focus on the role of B and T cells, immuno-senescence, the brain lymphatic system (BLS), gut-brain axis alterations, and dysfunctional interactions between neurons, microglia and astrocytes. We also outline a rational framework for identifying "druggable" targets for multi-mechanistic small molecules with therapeutic potential against AD.

Learning from anti‐tau antibody clinical trials using computer simulation of spatial tau propagation

AbstractBackgroundBased on the tau spreading hypothesis, anti‐tau antibodies have been developed that can bind to and eliminate the misfolded tau protein during the short extracellular period. However, trials with tau antibodies have come up short in improving clinical outcome in Progressive Supranuclear Palsy (PSP) or Alzheimer’s Disease (AD). It is unclear whether the negative outcomes were due to insufficient target engagement and to what extent the change of tau CSF biomarkers reflected the brain pharmacodynamics.MethodA Quantitative Systems Pharmacology (QSP) computer platform of tau biology has been developed including tau species diversity and their respective concentration, neuronal activity‐dependent tau secretion, tau binding to membrane surface receptors HSPG and LRP1, tau‐antibody binding and subsequent internalization of tau at the synaptic cleft. This model is combined with a Physiology‐Based PharmacoKinetic (PBPK) model to derive brain target exposure of tau antibodies. In addition, a PBPK model is used to simulate the level of plasma and CSF biomarkers.ResultThe platform was calibrated with preclinical in‐vitro cellular assays and after injection of brain extract in Transgene mouse models and was further humanized using published data on seed‐competent tau from postmortem AD brain at different Braak stages. Combining the extracellular antibody exposure, the spatial dimensions and the dynamics of tau secretion, diffusion and binding to the membrane surface receptors, the model suggests that a very limited fraction (10‐20%) of misfolded tau protein can be captured by antibodies and cleared. Even less reduction (5‐10%) is predicted for Progressive Supranuclear Palsy due to the higher affinity of PSP‐4R tau for membrane surface receptors. The reductions in misfolded tau protein are greatest in earlier stages of the disease. With regard to epitope selection, we identify conditions where high specificity (i.e. monomeric vs misfolded tau) is superior to high sensitivity (affinity).ConclusionAdvanced Quantitative Systems Pharmacology computer modeling combining drug exposure dynamics with mechanistic modeling allows to (1) generate testable hypotheses for the outcomes of current therapeutic interventions, (2) support improved clinical trial designs in terms of dosing, patient selection, background amyloid therapy and disease stage and (3) ultimately prioritize targets for addressing tau pathology.

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation

Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms-unfolded protein response and integrated stress response. Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling invitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation, whereas inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the endoplasmic reticulum luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small-molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.

Populations of Tau Conformers Drive Prion-like Strain Effects in Alzheimer's Disease and Related Dementias.

Recent findings of diverse populations of prion-like conformers of misfolded tau protein expand the prion concept to Alzheimer’s disease (AD) and monogenic frontotemporal lobar degeneration (FTLD)-MAPT P301L, and suggest that distinct strains of misfolded proteins drive the phenotypes and progression rates in many neurodegenerative diseases. Notable progress in the previous decades has generated many lines of proof arguing that yeast, fungal, and mammalian prions determine heritable as well as infectious traits. The extraordinary phenotypic diversity of human prion diseases arises from structurally distinct prion strains that target, at different progression speeds, variable brain structures and cells. Although human prion research presents beneficial lessons and methods to study the mechanism of strain diversity of protein-only pathogens, the fundamental molecular mechanism by which tau conformers are formed and replicate in diverse tauopathies is still poorly understood. In this review, we summarize up to date advances in identification of diverse tau conformers through biophysical and cellular experimental paradigms, and the impact of heterogeneity of pathological tau strains on personalized structure- and strain-specific therapeutic approaches in major tauopathies.

Clinical Spectrum of Tauopathies.

Tauopathies are both clinical and pathological heterogeneous disorders characterized by neuronal and/or glial accumulation of misfolded tau protein. It is now well understood that every pathologic tauopathy may present with various clinical phenotypes based on the primary site of involvement and the spread and distribution of the pathology in the nervous system making clinicopathological correlation more and more challenging. The clinical spectrum of tauopathies includes syndromes with a strong association with an underlying primary tauopathy, including Richardson syndrome (RS), corticobasal syndrome (CBS), non-fluent agrammatic primary progressive aphasia (nfaPPA)/apraxia of speech, pure akinesia with gait freezing (PAGF), and behavioral variant frontotemporal dementia (bvFTD), or weak association with an underlying primary tauopathy, including Parkinsonian syndrome, late-onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), and amnestic syndrome. Here, we discuss clinical syndromes associated with various primary tauopathies and their distinguishing clinical features and new biomarkers becoming available to improve in vivo diagnosis. Although the typical phenotypic clinical presentations lead us to suspect specific underlying pathologies, it is still challenging to differentiate pathology accurately based on clinical findings due to large phenotypic overlaps. Larger pathology-confirmed studies to validate the use of different biomarkers and prospective longitudinal cohorts evaluating detailed clinical, biofluid, and imaging protocols in subjects presenting with heterogenous phenotypes reflecting a variety of suspected underlying pathologies are fundamental for a better understanding of the clinicopathological correlations.

Variation at the LRRK2 locus determines the rate of disease progression in pro- gressive supranuclear palsy

BackgroundThe genetic basis of variation in the rate of disease progression in primary tauopathies is poorly understood. Here, we have conducted a genome-wide association study (GWAS) of Progressive Supranuclear Palsy cases using survival as a marker of disease progression.MethodsTwo independent, deeply-phenotyped, PSP cohorts of European ancestry underwent genotyp- ing and SNP imputation. Standard data quality control steps were used, including a MAF threshold of 1%. We used a cox-proportional hazards survival model GWAS that adjusted for sex, age at motor symptom onset, PSP phenotype and ethnicity (first three principal components).Results1,001 PSP cases (2011 case-control GWAS, n=424; UCL PSP cohort, n=577) and 4,817,946 SNPs passed quality control steps and were available for analysis. We found a genome-wide significant signal on chromosome 12 with the lead SNP identified as rs2242367 (hazard ratio = 2.24, p-value = 7.5x10-10). This signal replicated when each independent cohort was analysed separately. The risk allele at this SNP was associated with a 1 year reduction in survival. eQTL analyses revealed that rs2242367 and its tagging SNPs are eQTLs for LRRK2 expression in whole blood and brain.ConclusionsWe hypothesise that the whole blood eQTL signal may impact on monocyte-derived micro- glia-like cells and that increased LRRK2 expression may result in a reactive microglia-induced pro-inflam- matory state which drives ongoing accumulation of misfolded tau protein and clinical disease progression.e.jabbari@ucl.ac.uk