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

Abstract

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 β-amyloid (Aβ) was directly involved in PAK signaling deficits and drebrin loss in Aβ oligomer–treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Aβ 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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Figure 1: Selective and massive reduction in PAK amounts and activity in the hippocampus and temporal cortex in Alzheimer disease (AD).
Figure 2: pPAK, cofilin and drebrin changes in the hippocampus of individuals with Alzheimer disease.
Figure 3: pPAK and cofilin pathologies in 22-month-old Appswe Tg2576 mice.
Figure 4: pPAK and drebrin losses were reproduced in vitro in soluble Aβ1–42 oligomer-treated hippocampal neurons.
Figure 5: Wild-type (WT), but not kinase-dead (KD), PAK limits Aβ oligomer–induced drebrin loss.
Figure 6: PAK inhibition causes drebrin and cofilin pathologies and behavioral deficits.

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Acknowledgements

We thank the patients and families who generously donated brain tissue samples for this research via the Alzheimer Disease Research Center Neuropathology Cores of the University of California at Los Angeles (H. Vinters, P50 AG 16570) and the University of Southern California (C.A. Miller [P50 AG05142]). We also thank P.P. Chen, P. Kim and M. Simmons for technical expertise. This work was supported by a Veterans Affairs Merit grant (to G.M.C.), the US National Institutes of Health (RO1 AG13741 and NS43946 to G.M.C., AG10685 and AG16793 to S.A.F., and AG022080 to M.H.-W.), the University of California Los Angeles Alzheimer's Disease Research Center (PO1 AG16570, project to G.M.C.) and the UCLA Claude Pepper Older Americans Independence Center funded by the National Institute of Aging (AG10415 to L.Z.).

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Correspondence to Greg M Cole.

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Supplementary information

Supplementary Fig. 1

A schematic diagram, summarizing the overlapping features of mental retardation (MR), Alzheimer's disease (AD) and human APPswe Tg2576 transgenic mice. (PDF 61 kb)

Supplementary Fig. 2

PAK inhibition by PAK18 in hippocampal neurons. (PDF 165 kb)

Supplementary Fig. 3

A schematic diagram, summarizing the PAK-LIM kinase-cofilin-drebrin signaling pathways. (PDF 60 kb)

Supplementary Note (PDF 90 kb)

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Zhao, L., Ma, QL., Calon, F. et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci 9, 234–242 (2006). https://doi.org/10.1038/nn1630

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