p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis.
Defects in dendritic spines and synapses contribute to cognitive deficits in mental retardation syndromes and, potentially, Alzheimer disease. p21-activated kinases (PAKs) regulate actin filaments and morphogenesis of dendritic spines regulated by the Rho family GTPases Rac and Cdc42. We previously reported that active PAK was markedly reduced in Alzheimer disease cytosol, accompanied by downstream loss of the spine actin-regulatory protein Drebrin. beta-Amyloid (Abeta) oligomer was implicated in PAK defects. Here we demonstrate that PAK is aberrantly activated and translocated from cytosol to membrane in Alzheimer disease brain and in 22-month-old Tg2576 transgenic mice with Alzheimer disease. This active PAK coimmunoprecipitated with the small GTPase Rac and both translocated to granules. Abeta42 oligomer treatment of cultured hippocampal neurons induced similar effects, accompanied by reduction of dendrites that were protected by kinase-active but not kinase-dead PAK. Abeta42 oligomer treatment also significantly reduced N-methyl-d-aspartic acid receptor subunit NR2B phosphotyrosine labeling. The Src family tyrosine kinase inhibitor PP2 significantly blocked the PAK/Rac translocation but not the loss of p-NR2B in Abeta42 oligomer-treated neurons. Src family kinases are known to phosphorylate the Rac activator Tiam1, which has recently been shown to be Abeta-responsive. In addition, anti-oligomer curcumin comparatively suppressed PAK translocation in aged Tg2576 transgenic mice with Alzheimer amyloid pathology and in Abeta42 oligomer-treated cultured hippocampal neurons. Our results implicate aberrant PAK in Abeta oligomer-induced signaling and synaptic deficits in Alzheimer disease.
Ma
Qiu-Lan
QL
Department of Medicine, UCLA, Los Angeles, California, USA.
Yang
Fusheng
F
Calon
Frédéric
F
Ubeda
Oliver J
OJ
Hansen
James E
JE
Weisbart
Richard H
RH
Beech
Walter
W
Frautschy
Sally A
SA
Cole
Greg M
GM
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000737:chemistry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D054462:p21-Activated Kinases / Q000737:chemistry*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D054462:p21-Activated Kinases; D020558:GTP Phosphohydrolases; D020744:rac GTP-Binding Proteins