Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease

Lixia Zhao^1, 2, Qiu-Lan Ma^1, 2, Frédéric Calon^3, 4, Marni E Harris-White^1, 2, 5, Fusheng Yang^1, 2, Giselle P Lim^1, 2, Takashi Morihara⁶, Oliver J Ubeda^1, 2, Surendra Ambegaokar^1, 2, James E Hansen^1, 2, Richard H Weisbart^1, 2, Bruce Teter^1, 2, 5, Sally A Frautschy^{1, 2, 5, 7} & Greg M Cole^{1, 2, 5, 7}

¹  Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda, California 91343, USA.

²  Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.

³  Molecular Endocrinology & Oncology Research Center, Laval University Medical Center (CHUL), Quebec, Quebec G1V 4G2, Canada.

⁴  Faculty of Pharmacy, Laval University, Quebec, Quebec G1K 7P4, Canada.

⁵  Geriatric Research, Education and Clinical Center, Sepulveda, California 91343, USA.

⁶  Department of Post-Genomics and Disease, Division of Psychiatry and Behavioral Proteomics, School of Medicine, Osaka University, Japan.

⁷  Department of Neurology, University of California Los Angeles, Los Angeles, California 90095, USA.

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 -amyloid (A) was directly involved in PAK signaling deficits and drebrin loss in A oligomer–treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher A 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.

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