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 β‐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.

p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis

“…APP itself binds PAK through APP C-terminal domains requiring Asp-664 and is another candidate receptor that may be involved in age-dependent PAK signaling alterations similar to those we describe. PAK, LTP, and cognitive deficits are correlated in amyloid-accumulating APP Tg mice lacking the C-terminal Asp-664 mutation (47). These results support the hypothesis that aberrant PAK signaling is involved in LTP and cognitive deficits.…”

“…Tiam1 activation can be achieved by phosphorylation from elevated calcium acting through CaMKII, but PAK is eventually inhibited by calcium-induced calpain activation of Cdk5 (50). PAK could also be activated through direct interaction with candidate A␤ receptors (X), for example, the amyloid precursor protein (47) or indirectly via Src/Fyn activation of Tiam1. Although the A␤ receptors are not clearly established, A␤-mediated in vivo synaptotoxicity and in vitro LTP deficits are both Fyn kinase- (32,33) and NMDA receptor-dependent (1, 2).…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…Until recently, APP was an orphan receptor, yet it was recently proposed as a netrin-1 receptor (Lourenco et al, 2009). In addition, APP is known to be cleaved in its intracellular domain by caspase, thus yielding a toxic fragment (Nguyen et al, 2008). Whether APP is a netrin-1 DR remains an intriguing question.…”

Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding

“…In the context of neurodegeneration, caspase-6 cleaves a compelling set of neuronal substrates, including microtubule-associated protein Tau (19), amyloid precursor protein (20), presenilin I and II (20), polyglutamine-expanded and native huntingtin protein (21), and Parkinson disease protein 7 (PARK7), also known as protein deglycase DJ-1 (22). Caspase-6 is considered a promising molecular target for neurodegeneration treatments because cleavage of these neuronal substrates plays key roles in the pathophysiological outcome in Alzheimer's (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), Huntington's (21, 34 -40), and Parkinson's diseases (22). Thus, a full understanding of caspase-6 structure and its relation to function is central to achieving caspase-6-specific regulation in neurodegeneration.…”