Interaction between Aβ peptide and α synuclein:: Molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease

Amyloidogenic proteins (A beta peptide) in Alzheimer's disease (AD) and alpha-synuclein (alpha-Syn) in Parkinson's disease (PD) are typically soluble monomeric precursors, which undergo remarkable conformational changes and culminate in the form of aggregates in diseased condition. Overlap of clinical and neuropathological features of both AD and PD are observed in dementia with Lewy body (DLB) disease, the second most common form of dementia after AD. The identification of a 35-amino acid fragment of alpha-Syn in the amyloid plaques in DLB brain have raised the possibility that A beta and alpha-Syn interact with each other. In this report, the molecular interaction of alpha-Syn with A beta 40 and/or A beta 42 are investigated using multidimensional NMR spectroscopy. NMR data in the membrane mimic environment indicate specific sites of interaction between membrane-bound alpha-Syn with A beta peptide and vice versa. These A beta-alpha-Syn interactions are demonstrated by reduced amide peak intensity or change in chemical shift of amide proton of the interacting proteins. Based on NMR results, the plausible molecular mechanism of overlapping pathocascade of AD and PD in DLB due to interactions between alpha-Syn and A beta is described. To the best of our knowledge, it is the first report using multidimensional NMR spectroscopy that elucidates molecular interactions between A beta and alpha-Syn which may lead to onset of DLB.