Examining the mechanisms that link β-amyloid and α-synuclein pathologies

Samuel E Marsh,Mathew Blurton-Jones

doi:10.1186/alzrt109

Samuel E Marsh, Mathew Blurton-Jones

Open Access

https://doi.org/10.1186/alzrt109

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Abstract

β-amyloid (Aβ) and α-synuclein (α-syn) are aggregation-prone proteins typically associated with two distinct neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease. Yet α-syn was first found in association with AD plaques several years before being linked to Parkinson's disease or Lewy body formation. Nowadays, a large subset of AD patients (~50%) is well recognized to co-exhibit significant α-syn Lewy body pathology. Unfortunately, these AD Lewy body variant patients suffer from additional symptoms and an accelerated disease course. Basic research has begun to show that Aβ and α-syn may act synergistically to promote the aggregation and accumulation of each other. While the exact mechanisms by which these proteins interact remain unclear, growing evidence suggests that Aβ may drive α-syn pathology by impairing protein clearance, activating inflammation, enhancing phosphorylation, or directly promoting aggregation. This review examines the interactions between Aβ and α-syn and proposes potential mechanistic links between Aβ accumulation and α-syn pathogenesis.

Highlights

Protein misfolding and aggregation play a key role in many neurodegenerative disorders
The pathological identification of Aβ plaques and neurofibrillary tangles versus Lewy bodies has historically been used to distinguish between Alzheimer’s disease (AD) and the dementing forms of Lewy body disease
The postmortem identification of these patients is increasing as examination of all three proteins becomes more widely employed [8]. This subpopulation of patients – often termed as those with the Lewy body variant of Alzheimer’s disease (AD-LBV) – exhibit more rapid cognitive decline and shortened survival times compared with pure AD cases [9,10,11,12]

Summary

Introduction

Protein misfolding and aggregation play a key role in many neurodegenerative disorders. Two other pathological results of interest are that AD-LBV mice develop increased levels of insoluble Aβ42 tau at younger ages than 3xTg-AD mice This model uses mutant transgenes, the results provide important additional evidence that Aβ, tau, and α-syn can interact synergistically to accelerate pathogenesis and cognitive decline. Studies support several putative mechanisms by which β-amyloid (Aβ) and α-synuclein (α-syn) may interact to enhanced pathology and cognitive decline Such mechanisms include (left to right): chronic inflammation and microglial activation induced by both Aβ and α-syn; direct interactions and hybrid oligomerization of Aβ and α-syn; Aβ-induced kinase activation and α-syn phosphorylation; impairment of proteasome and autophagy degradation pathways; and Aβ-induced phosphorylation of tau leading to tau-mediated enhancement of α-syn aggregation. If direct interactions between Aβ and α-syn do play a role in AD-LBV pathogenesis, it will be important to understand why these interactions occur only in some patients and brain regions but not in others

Conclusions

Selkoe DJ

Findings

23. Jellinger KA