Soluble alpha-synuclein oligomers are associated with reduced synapsin expression and enhanced cognitive decline in Alzheimer's disease

Abstract

We recently proposed that soluble, intraneuronal alpha-synuclein (alpha-Syn) might modulate Alzheimer's disease (AD) pathophysiology in the absence of Lewy body (LB) pathology. With mounting evidence indicating that oligomeric forms of aggregation-prone proteins such as A-beta, tau and alpha-Syn may be the major bioactive deleterious agents involved in AD, frontotemporal dementia and Parkinson's disease, we sought to identify the nature of the soluble alpha-Syn species elevated in AD and to determine the relative contribution of soluble alpha-Syn oligomers to AD-associated cognitive deficits. Using enzyme-linked immunosorbent assays designed to detect oligomeric alpha-Syn in our well-characterized human cohort, we found elevated levels of soluble alpha-Syn oligomers (o-alpha-Syn) in AD brains compared to aged-matched controls in the absence of LB cytopathology. Upon finical measurements of soluble alpha-Syn in subjects with AD, we not only detected 2 forms of monomeric alpha-Syn but also apparent multimers of each monomer. Unexpectedly, only a subset of soluble o-alpha-Syn species was elevated intracellularly while extracellular o-alpha-Syn remained unchanged. Multivariate analyses revealed that the respective abundance of selective low molecular weight o-alpha-Syn was associated with cognitive deficits in multiple domains. Finally, we found that elevating o-alpha-Syn in an AD mouse model triggered a selective decrease in synapsins and exacerbated A-beta-induced cognitive deficits. Altogether, our data support differential roles for soluble, intraneuronal alpha-Syn oligomers in Alzheimer's disease, which could extend to other synucleinopathies.