The pathological cascade proposed in this news story—initiated by calpain activation and p35 cleavage to p25—is provocative, but should be viewed in the context of other calpain findings. The hypothesis that the inevitable outcome of p25-mediated phosphorylation of APP is increased Aβ generation in endosomes needs to be reconciled with the recent observations of Mathews at el.: that calpain inhibition, not activation, increases endosomal β-cleavage of APP and Aβ42 generation.⁽¹⁾ The phosphorylation of APP may well turn out to influence its trafficking and processing, but the calpain-p25 pathway is just one of several routes by which calpains might influence APP and cytoskeleton phosphorylation or processing and mediate cell death.

For example, data from our lab and others also implicate the calpain-PKC pathway in AD.^(2,3) Calpains are well-known to activate protein kinase C and, when persistently activated, they lower PKC levels. Lowered PKC activity, which is observed in the brains of Alzheimer’s patients, is associated with increased Aβ and reduced...  Read more

The pathological cascade proposed in this news story—initiated by calpain activation and p35 cleavage to p25—is provocative, but should be viewed in the context of other calpain findings. The hypothesis that the inevitable outcome of p25-mediated phosphorylation of APP is increased Aβ generation in endosomes needs to be reconciled with the recent observations of Mathews at el.: that calpain inhibition, not activation, increases endosomal β-cleavage of APP and Aβ42 generation.⁽¹⁾ The phosphorylation of APP may well turn out to influence its trafficking and processing, but the calpain-p25 pathway is just one of several routes by which calpains might influence APP and cytoskeleton phosphorylation or processing and mediate cell death.

For example, data from our lab and others also implicate the calpain-PKC pathway in AD.^(2,3) Calpains are well-known to activate protein kinase C and, when persistently activated, they lower PKC levels. Lowered PKC activity, which is observed in the brains of Alzheimer’s patients, is associated with increased Aβ and reduced APPs production in neurons exposed to PKC inhibitors. That PKC also modulates endocytosis suggests a potential link to the endosomal abnormalities that develop very early in AD. Moreover, PKC activation promotes tau phosphorylation in part through mitogen-activated protein kinase (MAPK). Because both cdk 5 and jnk 3 phosphorylate T668 of APP,^(4,5) it would not be surprising if APP is a potential target of other proline-directed kinases, including MAPK, under pathological conditions.

Calpain's known activity toward a broad array of substrates, including other kinases and phosphatases, may influence APP metabolism in still other ways. These pervasive effects explain why calpain activation can mediate neurodegeneration either directly (eg., Wallerian degeneration) or through several pathways leading to necrosis or apoptosis.^(2,3) In sum, the data emerging since we first showed a decade ago that brain calpains are activated in AD potentially link disparate aspects of Alzheimer’s pathobiology to this protease but do not support at present a mechanism of amyloidogenic APP processing based solely on calpain activation. These observations do not make the Tsai group’s findings any less intriguing, but they do illustrate that calpain's involvement in AD is multifaceted and unlikely to be explained by modulation through a single protein kinase pathway.

References:
1. Mathews PM, Jiang Y, Schmidt SD, Grbovic OM, Mercken M, Nixon RA. J Biol Chem. 2002 Sep 27;277(39):36415-24.

2. Nixon RA. A ‘protease activation cascade’ in the pathogenesis of Alzheimer’s disease. In: Alzheimer’s Disease: A Compendium of Current Theories. Khachaturian ZS and Mesulam MM (eds.) Ann NY Acad Sci 2000; 924:117-131.

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