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Diffusible, highly bioactive oligomers represent a critical minority of soluble A? in Alzheimer's disease brain.

ABSTRACT: Significant data suggest that soluble A? oligomers play an important role in Alzheimer's disease (AD), but there is great confusion over what exactly constitutes an A? oligomer and which oligomers are toxic. Most studies have utilized synthetic A? peptides, but the relevance of these test tube experiments to the conditions that prevail in AD is uncertain. A few groups have studied A? extracted from human brain, but they employed vigorous tissue homogenization which is likely to release insoluble A? that was sequestered in plaques during life. Several studies have found such extracts to possess disease-relevant activity and considerable efforts are being made to purify and better understand the forms of A? therein. Here, we compared the abundance of A? in AD extracts prepared by traditional homogenization versus using a far gentler extraction, and assessed their bioactivity via real-time imaging of iPSC-derived human neurons plus the sensitive functional assay of long-term potentiation. Surprisingly, the amount of A? retrieved by gentle extraction constituted only a small portion of that released by traditional homogenization, but this readily diffusible fraction retained all of the A?-dependent neurotoxic activity. Thus, the bulk of A? extractable from AD brain was innocuous, and only the small portion that was aqueously diffusible caused toxicity. This unexpected finding predicts that generic anti-oligomer therapies, including A? antibodies now in trials, may be bound up by the large pool of inactive oligomers, whereas agents that specifically target the small pool of diffusible, bioactive A? would be more useful. Furthermore, our results indicate that efforts to purify and target toxic A? must employ assays of disease-relevant activity. The approaches described here should enable these efforts, and may assist the study of other disease-associated aggregation-prone proteins.

SUBMITTER: Hong W

PROVIDER: S-EPMC6647843 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer's disease brain.

Hong Wei W Wang Zemin Z Liu Wen W O'Malley Tiernan T TT Jin Ming M Willem Michael M Haass Christian C Frosch Matthew P MP Walsh Dominic M DM

Acta neuropathologica 20180423 1

Significant data suggest that soluble Aβ oligomers play an important role in Alzheimer's disease (AD), but there is great confusion over what exactly constitutes an Aβ oligomer and which oligomers are toxic. Most studies have utilized synthetic Aβ peptides, but the relevance of these test tube experiments to the conditions that prevail in AD is uncertain. A few groups have studied Aβ extracted from human brain, but they employed vigorous tissue homogenization which is likely to release insoluble ...[more]

PMID: 29687257

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Project description:Alzheimer's disease (AD) is characterized by progressive cognitive decline, increasingly attributed to neuronal dysfunction induced by amyloid-β oligomers (AβOs). Although the impact of AβOs on neurons has been extensively studied, only recently have the possible effects of AβOs on astrocytes begun to be investigated. Given the key roles of astrocytes in synapse formation, plasticity, and function, we sought to investigate the impact of AβOs on astrocytes, and to determine whether this impact is related to the deleterious actions of AβOs on synapses. We found that AβOs interact with astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro We further show that both murine and human astrocyte conditioned media (CM) increase synapse density, reduce AβOs binding, and prevent AβO-induced synapse loss in cultured hippocampal neurons. Both a neutralizing anti-transforming growth factor-β1 (TGF-β1) antibody and siRNA-mediated knockdown of TGF-β1, previously identified as an important synaptogenic factor secreted by astrocytes, abrogated the protective action of astrocyte CM against AβO-induced synapse loss. Notably, TGF-β1 prevented hippocampal dendritic spine loss and memory impairment in mice that received an intracerebroventricular infusion of AβOs. Results suggest that astrocyte-derived TGF-β1 is part of an endogenous mechanism that protects synapses against AβOs. By demonstrating that AβOs decrease astrocyte ability to protect synapses, our results unravel a new mechanism underlying the synaptotoxic action of AβOs in AD.SIGNIFICANCE STATEMENT Alzheimer's disease is characterized by progressive cognitive decline, mainly attributed to synaptotoxicity of the amyloid-β oligomers (AβOs). Here, we investigated the impact of AβOs in astrocytes, a less known subject. We show that astrocytes prevent synapse loss induced by AβOs, via production of transforming growth factor-β1 (TGF-β1). We found that AβOs trigger morphological and functional alterations in astrocytes, and impair their neuroprotective potential. Notably, TGF-β1 reduced hippocampal dendritic spine loss and memory impairment in mice that received intracerebroventricular infusions of AβOs. Our results describe a new mechanism underlying the toxicity of AβOs and indicate novel therapeutic targets for Alzheimer's disease, mainly focused on TGF-β1 and astrocytes.

Dataset Information

Diffusible, highly bioactive oligomers represent a critical minority of soluble A? in Alzheimer's disease brain.

Publications

Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer's disease brain.

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