Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease

Presenilin 1 mutations are associated with synucleinopathies, but their contribution to pathology is unclear. Winslow et al. reveal an interaction between presenilin 1 and alpha-synuclein in cognitively normal individuals, which is increased in patients with dementia with Lewy bodies, and familial Alzheimer's disease. The interaction may regulate alpha-synuclein levels and localization.A growing number of PSEN1 mutations have been associated with dementia with Lewy bodies and familial Alzheimer's disease with concomitant alpha-synuclein pathology. The objective of this study was to determine if PSEN1 plays a direct role in the development of alpha-synuclein pathology in these diseases. Using mass spectrometry, immunoelectron microscopy and fluorescence lifetime image microscopy based on Forster resonance energy transfer (FLIM-FRET) we identified alpha-synuclein as a novel interactor of PSEN1 in wild-type mouse brain tissue. The interaction of alpha-synuclein with PSEN1 was detected in post-mortem brain tissue from cognitively normal cases and was significantly increased in tissue from cases with dementia with Lewy bodies and familial Alzheimer's disease associated with known PSEN1 mutations. We confirmed an increased interaction of PSEN1 and alpha-synuclein in cell lines expressing well characterized familial Alzheimer's disease PSEN1 mutations, L166P and delta exon 9, and demonstrated that PSEN1 mutations associate with increased membrane association and accumulation of alpha-synuclein. Our data provides evidence of a molecular interaction of PSEN1 and alpha-synuclein that may explain the clinical and pathophysiological overlap seen in synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and some forms of Alzheimer's disease.