α-synuclein in the pathophysiology of Alzheimer's disease

The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid- (A) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein -synuclein (Syn), mainly associated with synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is involved in the pathophysiology of AD. Lewy-related pathology (LRP), primarily comprised of Syn, is present in a majority of autopsied AD brains, and higher levels of Syn in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD have been linked to cognitive decline. Recent studies also suggest that the asymptomatic accumulation of A plaques is associated with higher CSF Syn levels in subjects at risk of sporadic AD and in individuals carrying autosomal dominant AD mutations. Experimental evidence has further linked Syn mainly to tau hyperphosphorylation, but also to the pathological actions of A and the APOE epsilon 4 allele, the latter being a major genetic risk factor for both AD and DLB. In this review, we provide a summary of the current evidence proposing an involvement of Syn either as an active or passive player in the pathophysiological ensemble of AD, and furthermore describe in detail the current knowledge of Syn structure and inferred function.