α-synuclein in the pathophysiology of Alzheimer's disease

Abstract

The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), 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 αSyn, is present in a majority of autopsied AD brains, and higher levels of αSyn 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 Aβ plaques is associated with higher CSF αSyn levels in subjects at risk of sporadic AD and in individuals carrying autosomal dominant AD mutations. Experimental evidence has further linked αSyn mainly to tau hyperphosphorylation, but also to the pathological actions of Aβ and the APOEε4 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 αSyn either as an active or passive player in the pathophysiological ensemble of AD, and furthermore describe in detail the current knowledge of αSyn structure and inferred function.

Keywords: Alzheimer’s disease; Lewy pathology; tau; α-synuclein.

Fig. 1

The structures of αSyn. a Primary structure of αSyn. N-terminal residues are green, the non-amyloid component (NAC) residues are blue, C-terminal residues are grey and disease associated point mutations are red. b Molecular model of a crystal structure of micelle bound human αSyn, PDB 1XQ8[103]. Color scheme is same as in a. c Molecular model of a cryo-electron microscopy structure of four human αSyn proteins (residues 1-121) in a fibril, PDB 6H6B[104]. Color scheme is same as in a. Molecular models created using Deep View Swiss PDB Viewer [105]

Fig. 2

Known (solid lines) and hypothetical (dotted lines) mechanisms shuffling αSyn between the intra-and extracellular compartments with implications for the development of AD pathological lesions. The top left-hand side and middle of the figure depicts physiological processes taking place in the healthy neuron A, the middle of the figure (underneath the healthy neuron A) is the extra-neuronal space with an astrocyte. The bottom half and right-hand side of the figure depicts two independent neurons in pathophysiological conditions, neurons B and C respectively