Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease.
Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21-activated kinase (PAK) can lead to mental retardation and because PAK-cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin-regulatory protein drebrin, which cofilin removes from actin. We found that beta-amyloid (Abeta) was directly involved in PAK signaling deficits and drebrin loss in Abeta oligomer-treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Abeta production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.
Zhao
Lixia
L
Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda, California 91343, USA.
Ma
Qiu-Lan
QL
Calon
Frédéric
F
Harris-White
Marni E
ME
Yang
Fusheng
F
Lim
Giselle P
GP
Morihara
Takashi
T
Ubeda
Oliver J
OJ
Ambegaokar
Surendra
S
Hansen
James E
JE
Weisbart
Richard H
RH
Teter
Bruce
B
Frautschy
Sally A
SA
Cole
Greg M
GM
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D054462:p21-Activated Kinases
D051339:Actin Depolymerizing Factors; D016229:Amyloid beta-Peptides; D009479:Neuropeptides; C053386:drebrins; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases