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Evidence for sortilin modulating regional accumulation of human tau prions in transgenic mice.

ABSTRACT: Misfolding of tau proteins into prions and their propagation along neural circuits are thought to result in neurodegeneration causing Alzheimer's disease, progressive supranuclear palsy, chronic traumatic encephalopathy, and other tauopathies. Little is known about the molecular processes mediating tau prion replication and spreading in different brain regions. Using transgenic (Tg) mice with a neuronal promoter driving expression of human mutant (P301S) tau, we found that tau prion formation and histopathologic deposition is largely restricted to the hindbrain. Unexpectedly, tau mRNA and protein levels did not differ between the forebrain and hindbrain, suggesting that other factors modulating the conversion of tau into a prion exist and are region specific. Using a cell-based prion propagation assay, we discovered that tau prion replication is suppressed by forebrain-derived inhibitors, one of which is sortilin, a lysosomal sorting receptor. We also show that sortilin expression is higher in the forebrain than the hindbrain across the life span of the Tg mice, suggesting that sortilin, at least in part, inhibits forebrain tau prion replication in vivo. Our findings provide evidence for selective vulnerability in mice resulting in highly regulated levels of tau prion propagation, thus affording a model for identification of additional molecules that could mitigate the levels of tau prions in human tauopathies.

SUBMITTER: Johnson NR

PROVIDER: S-EPMC5754811 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Evidence for sortilin modulating regional accumulation of human tau prions in transgenic mice.

Johnson Noah R NR Condello Carlo C Guan Shenheng S Oehler Abby A Becker Julia J Gavidia Marta M Carlson George A GA Giles Kurt K Prusiner Stanley B SB

Proceedings of the National Academy of Sciences of the United States of America 20171204 51

Misfolding of tau proteins into prions and their propagation along neural circuits are thought to result in neurodegeneration causing Alzheimer's disease, progressive supranuclear palsy, chronic traumatic encephalopathy, and other tauopathies. Little is known about the molecular processes mediating tau prion replication and spreading in different brain regions. Using transgenic (Tg) mice with a neuronal promoter driving expression of human mutant (P301S) tau, we found that tau prion formation an ...[more]

PMID: 29203673

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Project description:BackgroundP301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO μPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism.MethodsTransgenic P301S (n = 33) and wild-type (n = 18) female mice were imaged by 18F-GE-180 TSPO μPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, 18F-fluordesoxyglucose (18F-FDG) μPET, and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO μPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-β mouse models.ResultsTSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11-23%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3-6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3-6.7 months.ConclusionsMonitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by μPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.

Project description:BACKGROUND:Alzheimer's disease (AD) is a devastating neurodegenerative disorder bearing multiple pathological hallmarks suggestive of complex cellular/molecular interplay during pathogenesis. Transgenic mice and nonhuman primates are used as disease models for mechanistic and translational research into AD; the extent to which these animal models recapitulate AD-type neuropathology is an issue of importance. Putative C-terminal fragments from sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) family, have recently been shown to deposit in the neuritic β-amyloid (Aβ) plaques in the human brain. METHODS:We set out to explore if extracellular sortilin neuropathology exists in AD-related transgenic mice and nonhuman primates. Brains from different transgenic strains and ages developed overt cerebral Aβ deposition, including the β-amyloid precursor protein and presenilin 1 double-transgenic (APP/PS1) mice at ~ 14 months of age, the five familial Alzheimer's disease mutations transgenic (5×FAD) mice at ~ 8 months, the triple-transgenic Alzheimer's disease (3×Tg-AD) mice at ~ 22 months, and aged monkeys (Macaca mulatta and Macaca fascicularis) were examined. Brain samples from young transgenic mice, middle-aged/aged monkeys, and AD humans were used as negative and positive pathological controls. RESULTS:The C-terminal sortilin antibody, which labeled senile plaques in the AD human cerebral sections, did not display extracellular immunolabeling in the transgenic mouse or aged monkey brain sections with Aβ deposition. In Western blot analysis, sortilin fragments ~ 15 kDa were not detectable in transgenic mouse cortical lysates, but they occurred in control AD lysates. CONCLUSIONS:In reference to their human brain counterparts, neuritic plaques seen in transgenic AD model mouse brains represent an incomplete form of this AD pathological hallmark. The species difference in neuritic plaque constituents also indicates more complex secondary proteopathies in the human brain relative to rodents and nonhuman primates during aging and in AD.

Project description:IntroductionAlzheimer's disease is partially characterized by the progressive accumulation of aggregated tau-containing neurofibrillary tangles. Although the association between accumulated tau, neurodegeneration, and cognitive decline is critical for disease understanding and clinical trial design, we still lack robust tools to predict individualized trajectories of tau accumulation. Our objective was to assess whether brain imaging biomarkers of flortaucipir-positron emission tomography (PET), in combination with clinical and genomic measures, could predict future pathological tau accumulation.MethodsWe quantified the disease profile of participants (N = 276) using a comprehensive set of descriptors, including clinical/demographic (age, diagnosis, amyloid status, sex, race, ethnicity), genetic (apolipoprotein E [APOE]-ε4), and flortaucipir-PET imaging measures (regional flortaucipir standardized uptake value ratio [SUVr] and comprehensive radiomic texture features extracted from Automated Anatomical Labeling template regions). We trained an AdaBoost machine learning algorithm in a 2:1 split train-test configuration to derive a prognostic index that (i) stratifies individualized brain regions including global (AD-signature region) and lobar regions (frontal, occipital, parietal, temporal) into stable/slow- and fast-progressors based on future tau accumulation, and (ii) forecasts individualized regional annualized-rate-of-change in flortaucipir-PET SUVr. Further, we developed an adaptive model incorporating flortaucipir-PET measurements from the baseline and intermediate timepoints to predict annualized-rate-of-change.ResultsIn binary classification for predicting stable/slow- versus fast-progressors, the area-under-the-receiver-operating-characteristic curve was 0.86 in the AD-signature region and 0.83, 0.82, 0.84, and 0.83 in frontal, occipital, parietal, and temporal regions, respectively. The trained models successfully predicted annualized-rate-of-change of flortaucipir-PET regional flortaucipir SUVr in AD-signature and lobar regions (Pearson-correlation [R]: AD-signature = 0.73; frontal = 0.73; occipital = 0.71; parietal = 0.70; temporal = 0.69). The models' performance in predicting annualized-rate-of-change slightly increased when imaging features from intermediate timepoints were used in the adaptive setting (R: AD-signature = 0.79; frontal = 0.87; occipital = 0.83; parietal = 0.74; temporal = 0.82).DiscussionTaken together, our results propose a robust approach to predict future tau accumulation that may improve the ability to enroll, stratify, and gauge efficacy in clinical trial participants.HighlightsMachine learning predicts the future rate of tau accumulation in Alzheimer's disease.Tau prediction in lobar/global regions benefits from diverse multimodal features.This prognostic index can serve as a sensitive tool for patient stratification.

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Evidence for sortilin modulating regional accumulation of human tau prions in transgenic mice.

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Evidence for sortilin modulating regional accumulation of human tau prions in transgenic mice.

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