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Abstract
Presenilin 1 (PS1) plays a critical role in the γ-secretase processing of the amyloid precursor protein to generate the β-amyloid peptide, which accumulates in plaques in the pathogenesis of Alzheimer's disease (AD). Mutations in PS1 cause early onset AD, and proteins that interact with PS1 are of major functional importance. We report here the coimmunoprecipitation of PS1 and acetylcholinesterase (AChE), an enzyme associated with amyloid plaques. Binding occurs through PS1 N-terminal fragment independent of the peripheral binding site of AChE. Subcellular colocalization of PS1 and AChE in cultured cells and coexpression patterns of PS1 and AChE in brain sections from controls and subjects with sporadic or familial AD indicated that PS1 and AChE are located in the same intracellular compartments, including the perinuclear compartments. A PS1-A246E pathogenic mutation expressed in transgenic mice leads to decreased AChE activity and alteration of AChE glycosylation and the peripheral binding site, which may reflect a shift in protein conformation and disturbed AChE maturation. In both the transgenic mice and humans, mutant PS1 impairs coimmunoprecipitation with AChE. The results indicate that PS1 can interact with AChE and influence its expression, supporting the notion of cholinergic-amyloid interrelationships.
ACKNOWLEDGMENTS
We thank M. Calero (Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain) for helpful advice; S. Ramón y Cajal and N. Torán (Department of Pathology, Hospital Vall d'Hebron, Barcelona, Spain) for assistance with accessing human embryonic samples; and R. Bruno, R. Rivera, and M. Ródenas for technical assistance.
M.-X.S. is a fellow of CSIC (MEC) from Spain. G.E. and J.G.C. are supported by the Australian NHMRC. This study was supported by grants from the la Caixa Foundation, FIS (grants 03/0038 and 06/0181), and CIBERNED, ISC-III (Spain), to J.S.-V.