Presenilin 1 interacts with acetylcholinesterase and alters its enzymatic activity and glycosylation.
Presenilin 1 (PS1) plays a critical role in the gamma-secretase processing of the amyloid precursor protein to generate the beta-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.
Silveyra
María-Ximena
MX
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Crta. Alicante-Valencia Km.87, Sant Joan d'Alacant E-03550, Spain. j.saez@umh.es
Evin
Geneviève
G
Montenegro
María-Fernanda
MF
Vidal
Cecilio J
CJ
Martínez
Salvador
S
Culvenor
Janetta G
JG
Sáez-Valero
Javier
J
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D005260:Female; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014020:Tissue Extracts / Q000378:metabolism
D053764:Presenilin-1; D014020:Tissue Extracts; D000110:Acetylcholinesterase