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A? accumulation causes MVB enlargement and is modelled by dominant negative VPS4A.

ABSTRACT: Alzheimer's disease (AD)-linked ?-amyloid (A?) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on A? accumulation and tau pathology are incompletely understood.MVB size and A? fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy. MVB-dysfunction, modelled by expression of dominant negative VPS4A (dnVPS4A), was analysed by biochemical methods and exosome isolation.Here we show that AD transgenic neurons have enlarged MVBs compared to wild type neurons. Uptake of exogenous A? also leads to enlarged MVBs in wild type neurons and generates fibril-like structures in endocytic vesicles. With time fibrillar oligomers/fibrils can extend out of the endocytic vesicles and are eventually detectable extracellularly. Further, endosomal sorting complexes required for transport (ESCRT) components were found associated with amyloid plaques in AD transgenic mice. The phenotypes previously reported in AD transgenic neurons, with net increased intracellular levels and reduced secretion of A?, were mimicked by blocking recycling of ESCRT-III by dnVPS4A. DnVPS4A further resembled AD pathology by increasing tau phosphorylation at serine 396 and increasing markers of autophagy.We demonstrate that A? leads to MVB enlargement and that amyloid fibres can form within the endocytic pathway of neurons. These results are consistent with the scenario of the endosome-lysosome system representing the site of initiation of A? aggregation. In turn, a dominant negative form of the CHMP2B-interacting protein VPS4A, which alters MVBs, leads to accumulation and aggregation of A? as well as tau phosphorylation, mimicking the cellular changes in AD.

SUBMITTER: Willen K

PROVIDER: S-EPMC5569475 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A.

Willén Katarina K Edgar James R JR Hasegawa Takafumi T Tanaka Nobuyuki N Futter Clare E CE Gouras Gunnar K GK

Molecular neurodegeneration 20170823 1

<h4>Background</h4>Alzheimer's disease (AD)-linked β-amyloid (Aβ) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Aβ accumulation and tau pathology are incompletely understood.<h4>Methods</h4>MVB size and Aβ fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent micr ...[more]

PMID: 28835279

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Project description:ObjectiveTo evaluate a novel β-amyloid (Aβ)-PET-based quantitative measure (Aβ accumulation index [Aβ index]), including the assessment of its ability to discriminate between participants based on Aβ status using visual read, CSF Aβ42/Aβ40, and post-mortem neuritic plaque burden as standards of truth.MethodsOne thousand one hundred twenty-one participants (with and without cognitive impairment) were scanned with Aβ-PET: Swedish BioFINDER, n = 392, [18F]flutemetamol; Alzheimer's Disease Neuroimaging Initiative (ADNI), n = 692, [18F]florbetapir; and a phase 3 end-of-life study, n = 100, [18F]flutemetamol. The relationships between Aβ index and standardized uptake values ratios (SUVR) from Aβ-PET were assessed. The diagnostic performances of Aβ index and SUVR were compared with visual reads, CSF Aβ42/Aβ40, and Aβ histopathology used as reference standards.ResultsStrong associations were observed between Aβ index and SUVR (R 2: BioFINDER 0.951, ADNI 0.943, end-of-life, 0.916). Both measures performed equally well in differentiating Aβ-positive from Aβ-negative participants, with areas under the curve (AUCs) of 0.979 to 0.991 to detect abnormal visual reads, AUCs of 0.961 to 0.966 to detect abnormal CSF Aβ42/Aβ40, and AUCs of 0.820 to 0.823 to detect abnormal Aβ histopathology. Both measures also showed a similar distribution across postmortem-based Aβ phases (based on anti-Aβ 4G8 antibodies). Compared to models using visual read alone, the addition of the Aβ index resulted in a significant increase in AUC and a decrease in Akaike information criterion to detect abnormal Aβ histopathology.ConclusionThe proposed Aβ index showed a tight association to SUVR and carries an advantage over the latter in that it does not require the definition of regions of interest or the use of MRI. Aβ index may thus prove simpler to implement in clinical settings and may also facilitate the comparison of findings using different Aβ-PET tracers.Classification of evidenceThis study provides Class III evidence that the Aβ accumulation index accurately differentiates Aβ-positive from Aβ-negative participants compared to Aβ-PET visual reads, CSF Aβ42/Aβ40, and Aβ histopathology.

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A? accumulation causes MVB enlargement and is modelled by dominant negative VPS4A.

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Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A.

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