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Signal transduction in Alzheimer disease: p21-activated kinase signaling requires C-terminal cleavage of APP at Asp664.

Abstract：

:The deficits in Alzheimer disease (AD) stem at least partly from neurotoxic beta-amyloid peptides generated from the amyloid precursor protein (APP). APP may also be cleaved intracellularly at Asp664 to yield a second neurotoxic peptide, C31. Previously, we showed that cleavage of APP at the C-terminus is required for the impairments seen in APP transgenic mice, by comparing elements of the disease in animals modeling AD, with (platelet-derived growth factor B-chain promoter-driven APP transgenic mice; PDAPP) versus without (PDAPP D664A) a functional Asp664 caspase cleavage site. However, the signaling mechanism(s) by which Asp664 contributes to these deficits remains to be elucidated. In this study, we identify a kinase protein, recently shown to bind APP at the C-terminus and to contribute to AD, whose activity is modified in PDAPP mice, but normalized in PDAPP D664A mice. Specifically, we observed a significant increase in nuclear p21-activated kinase (isoforms 1, 2, and or 3; PAK-1/2/3) activation in hippocampus of 3 month old PDAPP mice compared with non-transgenic littermates, an effect completely prevented in PDAPP D664A mice. In contrast, 13 month old PDAPP mice displayed a significant decrease in PAK-1/2/3 activity, which was once again absent in PDAPP D664A mice. Similarly, in hippocampus of early and severe AD subjects, there was a progressive and subcellular-specific reduction in active PAK-1/2/3 compared with normal controls. Interestingly, total PAK-1/2/3 protein was increased in early AD subjects, but declined in moderate AD and declined further, to significantly below that of control levels, in severe AD. These findings are compatible with previous suggestions that PAK may be involved in the pathophysiology of AD, and demonstrate that both early activation and late inactivation in the murine AD model require the cleavage of APP at Asp664.

journal_name

J Neurochem

journal_title

Journal of neurochemistry

authors

Nguyen TV,Galvan V,Huang W,Banwait S,Tang H,Zhang J,Bredesen DE

doi

10.1111/j.1471-4159.2007.05031.x

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

1065-80

issue

eissn

0022-3042

issn

1471-4159

pii

JNC5031

journal_volume

104

pub_type

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Signal transduction in Alzheimer disease: p21-activated kinase signaling requires C-terminal cleavage of APP at Asp664.