Dataset Information

Extracellular Sortilin Proteopathy Relative to ?-Amyloid and Tau in Aged and Alzheimer's Disease Human Brains.

ABSTRACT: Amyloid plaques and neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer's disease (AD) related to ?-amyloid (A?) deposition and intraneuronal phosphorylated tau (pTau) accumulation. Sortilin C-terminal fragments (shortened as "sorfra") can deposit as senile plaque-like lesions within AD brains. The course and pattern of sorfra plaque formation relative to A? and pTau pathogenesis remain unknown. In the present study, cerebral and subcortical sections in postmortem human brains (n = 46) from aged and AD subjects were stained using multiple markers (6E10, ?-secretase 1, pTau, and sortilin antibodies, as well as Bielschowsky silver stain). The course and pattern of sorfra plaque formation relative to Thal A? and Braak NFT pathogenic stages were determined. Sorfra plaques occurred in the temporal, inferior frontal and occipital neocortices in cases with Thal 1 and Braak III stages. They were also found additionally in the hippocampal formation, amygdala, and associative neocortex in cases with Thal 2-4 and Braak IV-V. Lastly, they were also found in the primary motor, somatosensory, and visual cortices in cases with Thal 4-5 and Braak VI. Unlike A? and pTau pathologies, sorfra plaques did not occur in subcortical structures in cases with A?/pTau lesions in Thal 3-5/Braak IV-VI stages. We establish here that sorfra plaques are essentially a cerebral proteopathy. We believe that the development of sorfra plaques in both cortical and hippocampal regions proceeds in a typical spatiotemporal pattern, and the stages of cerebral sorfra plaque formation partially overlap with that of A? and pTau pathologies.

SUBMITTER: Tu T

PROVIDER: S-EPMC7236809 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Extracellular Sortilin Proteopathy Relative to β-Amyloid and Tau in Aged and Alzheimer's Disease Human Brains.

Tu Tian T Jiang Juan J Zhang Qi-Lei QL Wan Lily L Li Ya-Nan YN Pan Aihua A Manavis Jim J Yan Xiao-Xin XX

Frontiers in aging neuroscience 20200512

Amyloid plaques and neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer's disease (AD) related to β-amyloid (Aβ) deposition and intraneuronal phosphorylated tau (pTau) accumulation. <i>Sor</i>tilin C-terminal <i>fra</i>gments (shortened as "sorfra") can deposit as senile plaque-like lesions within AD brains. The course and pattern of sorfra plaque formation relative to Aβ and pTau pathogenesis remain unknown. In the present study, cerebral and subcortical sections in postmortem huma ...[more]

PMID: 32477092

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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 ?-amyloid (A?) 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 A? deposition, including the ?-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 A? 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:Alzheimer's disease (AD) is characterized by the accumulation of amyloid-? (A?) as senile plaques and cerebral amyloid angiopathy, and hyperphosphorylated tau (hp-tau) as neurofibrillary tangles in the brain. The AD-related pathology has been reported in several non-human animals, and most animals develop only the A? or tau pathology. We herein describe the A? and hp-tau pathology in the brains of aged pinniped species (seal, sea lion, and walrus). Molecular analyses revealed that the sequence of pinniped A? was identical to that of human A?. Histopathological examinations detected argyrophilic plaques composed of A? associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around A? plaques. A? deposits were observed in the blood vessel walls of the meninges and cerebrum. Pinniped tau protein was physiologically subjected to alternative splicing at exons 2, 3, and 10, and presented as five isoforms: two 3-repeat tau isoforms (1N3R, 2N3R) and three 4-repeat tau isoforms (0N4R, 1N4R, 2N4R); 0N3R tau isoform was absent. Histopathological examinations revealed argyrophilic fibrillar aggregates composed of hp-tau in the neuronal somata and neurites of aged pinniped brains. Few hp-tau aggregates were found in oligodendrocytes and microglia. Biochemically, hp-tau of the 3-repeat and 4-repeat isoforms was detected in brain sarkosyl-insoluble fractions. A? and hp-tau both predominantly accumulated in the neocortex, particularly the frontal cortex. Furthermore, the activation of GSK-3? was detected within cells containing hp-tau aggregates, and activated GSK-3? was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with A? deposition, the activation of GSK-3? contributes to hp-tau accumulation in pinniped brains. Here, we report that pinniped species naturally accumulate A? and tau with aging, similar to the human AD pathology.

Project description:Functionally related brain regions are selectively vulnerable to Alzheimer's disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer's disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer's disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer's disease dementia, we found several distinct spatial patterns of tau deposition, including 'Braak-like' and 'non-Braak-like', across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with 'non-Braak-like' patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer's disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer's disease.

Dataset Information

Extracellular Sortilin Proteopathy Relative to ?-Amyloid and Tau in Aged and Alzheimer's Disease Human Brains.

Publications

Extracellular Sortilin Proteopathy Relative to β-Amyloid and Tau in Aged and Alzheimer's Disease Human Brains.

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