Zhao, L. et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat. Neurosci. 9, 234-242

Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda, California 91343, USA.
Nature Neuroscience (Impact Factor: 16.1). 03/2006; 9(2):234-42. DOI: 10.1038/nn1630
Source: PubMed


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.

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    • "Because rods sequester virtually all of the cofilin within the local region of the neurite [118], they inhibit synaptic function [125] because cofilin plays an important role in both AMPA channel insertion and dendritic spine enlargement associated with longterm potentiation [126]. Although rods are induced by oligomers of synthetic human A 1-42 [121], Cu 2+ peroxide oxidation of synthetic human A increases its rod inducing efficacy by about 600 fold [127]. The cofilin-actin rods contribute to synaptic loss as evident from cultured neurons subjected to excitotoxic stress and A exposure. "
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    • "In a previous study of a similar set of AD and control cases, significant reductions in some synaptic proteins in AD hippocampus and ITC compared to control brain were observed [19] [20] and there is a well-documented loss of synapses in AD [25] [26] that would predict a correspondingly reduction in neuronal cofilin. Conversely, it has been postulated that greater levels of synaptic cofilin in AD contributes to the mechanism of dendritic pruning and synaptic loss, acting in conjunction with reduced levels of drebrin [2] [27], however our results do not support this as we did not observe increases in cofilin in preparations from AD compared with control brains. We note here that total protein levels do not necessarily reflect the percent of active cofilin which may still be affected. "
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    • "Drebrin, which is an actin stabilizing protein important for spine morphogenesis, has been observed to be significantly reduced in AD brain (70e95%) [22]. It has been shown that there is a reciprocal relationship between cofilin and drebrin levels in AD patient samples and in vitro experiments on cultured neurons suggest that cofilin competes for drebrin binding sites on actin filaments [20]. The same study also showed that overexpression of active PAK could rescue Ab induced loss of drebrin . "
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