Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease.
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Abstract
Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.
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Acknowledgements: This study was supported by the EPSRC grant 2594676 (HEW, SD), Alzheimer’s Society PhD studentship grant 396 (MM,SW), AMS grants SGL028\1097 (SMB), Parkinson’s UK grants F-1301 (H.M.), NIH grants AG047644 (D.M.H.) and NS090934 (D.M.H.), European Research Council Grant Number 669237 (D.K.), the Royal Society (D.K.), Dementia Research UK Pilot Award (S.D.), the UK Dementia Research Institute (DRI) at Cambridge (D.K.), Academy of Medical sciene springboard award SBF006\1038 (S.D.) and a UKRI Future Leaders Fellowship (Grant number MR/V023861/1) (A.O., A.U., and S.D.). The tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council and in part by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. We thank Sneha Rajan and Guy Soane for helping with western blot study. We also thank the Professor Maria Spillantini, University of Cambridge laboratory for providing the facilities and expertise for processing of the brain tissue used in these experiments. The Sheffield NIHR Biomedical Research Centre provided support for this study.
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2041-1723
