Accumulation of insoluble alpha-synuclein in dementia with Lewy bodies

The alpha-synuclein (alpha SN) protein is thought to play a central role in the pathogenesis of neurodegenerative diseases where it aggregates to form intracellular inclusions. We have used Western blotting to examine the exp ression levels and solubility of alpha SN in brain homogenates from dementi a with Lewy bodies (DLB), Parkinson's disease (PD), Alzheimer's disease (AD ), and normal controls using samples from the parahippocampus/transentorhin al cortex. Compared to controls, DLB brains accumulate significantly greate r amounts of sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble alpha S N but levels of TBS-soluble alpha SN did not change. Levels of synaptophysi n, a marker of synaptic integrity, were significantly lower in DLB cases th an in normal aged controls regardless of whether concurrent changes of AD w ere present. This limbic synaptic dysfunction may contribute to cognitive i mpairment in DLB. Whether aggregated alpha SN is a cause or effect of the d isease process in DLB and PD remains to be determined, but the presence of aggregated alpha SN is consistent with a pathogenesis similar to that assoc iated with aggregates of AP amyloid in AD. (C) 2000 Academic Press.