4.7 Article

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

Journal

NATURE NEUROSCIENCE
Volume 9, Issue 2, Pages 234-242

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/nn1630

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Funding

  1. NIA NIH HHS [P01 AG16570, P50 AG05142, AG16793, P50 AG 16570, P50 AG016570, R01 AG13741, AG10685, AG10415, R01 AG013741, R01 AG010685, AG022080] Funding Source: Medline
  2. NINDS NIH HHS [NS43946] Funding Source: Medline

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