Interaction between Aβ Peptide and α Synuclein: Molecular Mechanisms in Overlapping Pathology of Alzheimer’s and Parkinson’s in Dementia with Lewy Body Disease

Abstract

Amyloidogenic proteins (Abeta 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 Abeta and alpha-Syn interact with each other. In this report, the molecular interaction of alpha-Syn with Abeta40 and/or Abeta42 are investigated using multidimensional NMR spectroscopy. NMR data in the membrane mimic environment indicate specific sites of interaction between membrane-bound alpha-Syn with Abeta peptide and vice versa. These Abeta-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 Abeta is described. To the best of our knowledge, it is the first report using multidimensional NMR spectroscopy that elucidates molecular interactions between Abeta and alpha-Syn which may lead to onset of DLB.

Interactions of Pathological Hallmark Proteins

“…A␤ 42 effectively stimulates the oligomerization of ␣-synuclein (56), and vice versa, the ␣-synuclein promotes the oligomerization of A␤ 42 leading to its in vitro precipitation (57) and formation of hybrid ring-like structures (17). TPPP/p25 can also induce ␣-synuclein aggregation (23).…”

Neuropathological Alterations in Alzheimer Disease

“…Some studies have shown that underlying interactions between a-synuclein and Ab play a fundamental role in the pathogenesis of LBD (Lippa et al 1998;Hashimoto et al 2000;Masliah et al 2001b, Pletnikova et al 2005. Specifically, Ab promotes the oligomerization and toxic conversion of a-synuclein (Masliah et al 2001b;Mandal et al 2006), Ab exacerbates the deficits associated with a-synuclein accumulation, Ab and a-synuclein colocalize in membrane and caveolar fractions, and Ab stabilizes a-synuclein multimers that might form channel-like structures in the membrane (Tsigelny et al 2007(Tsigelny et al , 2008. Both lysosomal leakage (Nixon and Cataldo 2006) and oxidative stress (Smith et al 1996) appear to be involved in the process of neurotoxicity and pathological interactions between Ab and a-synuclein (Rockenstein et al 2005).…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Remarkably, there is also evidence that these various protein aggregates can interact with each other [29]. For example, Aβ promotes the aggregation of α-syn and tau in AD and DLB [30,31], α-syn and tau interact in the brain of patients with PD and DLB [32,33], α-syn and Aβ can form hetero-oligomers [34,35], and α-syn can modulate the fibrillization state of Aβ [36].…”