19 May 2000. The cysteine protease calpain cleaves the cdk5 regulator p35, releasing
a 25KD fragment that accumulates in the brains of people with Alzheimer’s disease.
What’s more, Aβ42 is among the factors that trigger this reaction, report Li-Huei
Tsai of Harvard Medical School and her coworkers in the May 18 Nature. These findings
follow on the heels of Tsai’s recent study, which established p25’s role in tau
hyperphosphorylation, cytoskeletal disruption, and apoptosis of cortical neurons
(see news story below, 8 December, 1999). That study raised the question which
conditions foster the fateful cleavage of p35 and which enzyme carries it out.
The present report answers these questions. Collaborating with Robert Friedlander,
also of Harvard Medical School, Tsai first discovered that transient focal ischemia
in mice induced p25 in the same side of the brain. (P25 has never been detected
in healthy brain.) Then her group showed that free radicals, glutamate, and
elevated intracellular calcium stimulate the conversion of p35 into p25 in cultured
primary neurons. Inhibitors of the calcium-dependent protease calpain inhibited
this reaction. Moreover, calpain cleaved p35 in brain lysates and, when assayed
with purified p35, it generated a cleavage product whose sequence was identical
to that of p25. Finally, the researchers found that Aβ42 leads to the generation
of p25, and that calpain inhibitors rescued Aβ-induced neuronal death of
Calpain has long been suspected to play a role in neurotoxicity. Randy Nixon,
now at New York University, reported in 1997 that its activated form accumulated
in neurofibrillary tangles, as well as pre-tangle structures, in neurons of
people with AD.
Given that agents of neurotoxicity-glutamate overexcitation, hypoxic stress,
and Aβ peptides-converge to alter calcium homeostasis in affected neurons,
Tsai suggests that calpain’s conversion of p35 into p25 represents one mechanism
by which these agents can lead to hyperphosphorylation of tau and cell death,
thus contributing to Alzheimer’s pathology. This mechanism represents an example
for how cdk5-a kinase essential to proper brain development and adult function-can
be corrupted into damaging neurons, the authors write.-Gabrielle Strobel.
Reference:Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 2000 May 18;405(6784):360-4. Abstract