Abstract
A decade following the paradigm-shifting concept that endogenous forms of soluble, non-fibrillar amyloid-β (Aβ) might constitute the major bioactive entity causing synaptic loss and cognitive decline in Alzheimer's disease (AD), our understanding of these oligomeric species still remains conspicuously superficial. The current lack of direct evaluation tools for each endogenous Aβ oligomer hampers our ability to readily address crucial question such as: (i) where they form and accumulate?; (ii) when they first appear in human brains and body fluids?; (iii) what is the longitudinal expression of these putative toxins during the course of the disease?; (iv) and how do these soluble Aβ assemblies alter synaptic and neuronal function in the brain? Despite these limitations, indirect ex vivo measurement and isolation from biological specimens has been possible and have allowed parsing out intrinsic differences between putative endogenous Aβ oligomers. In this review, I integrated recent findings and extrapolated emerging hypotheses derived from these studies with the hope to provide a clarified view on the putative role of endogenous Aβ oligomers in AD, with a particular emphasis on the timing at which these soluble species might act in the aging and diseased brain.
Highlights
Many neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease or frontotemporal dementias are characterised by the presence of abnormal protein aggregates in the brain
The current lack of direct evaluation tools for each endogenous Aβ oligomer hampers our ability to readily address crucial question such as: (i) where they form and accumulate?; (ii) when they first appear in human brains and body fluids?; (iii) what is the longitudinal expression of these putative toxins during the course of the disease?; (iv) and how do these soluble Aβ assemblies alter synaptic and neuronal function in the brain? Despite these limitations, indirect ex vivo measurement and isolation from biological specimens has been possible and have allowed parsing out intrinsic differences between putative endogenous Aβ oligomers
I integrated recent findings and extrapolated emerging hypotheses derived from these studies with the hope to provide a clarified view on the putative role of endogenous Aβ oligomers in Alzheimer’s disease (AD), with a particular emphasis on the timing at which these soluble species might act in the aging and diseased brain
Summary
A decade following the paradigm-shifting concept that endogenous forms of soluble, non-fibrillar amyloid-β (Aβ) might constitute the major bioactive entity causing synaptic loss and cognitive decline in Alzheimer’s disease (AD), our understanding of these oligomeric species still remains conspicuously superficial. The current lack of direct evaluation tools for each endogenous Aβ oligomer hampers our ability to readily address crucial question such as: (i) where they form and accumulate?; (ii) when they first appear in human brains and body fluids?; (iii) what is the longitudinal expression of these putative toxins during the course of the disease?; (iv) and how do these soluble Aβ assemblies alter synaptic and neuronal function in the brain? I integrated recent findings and extrapolated emerging hypotheses derived from these studies with the hope to provide a clarified view on the putative role of endogenous Aβ oligomers in AD, with a particular emphasis on the timing at which these soluble species might act in the aging and diseased brain
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