Increased production of neurotoxic forms of
amyloid beta-peptide (Abeta) and abnormalities in neuronal
calcium homeostasis play central roles in the pathogenesis of
Alzheimer's disease (AD). Notch, a membrane receptor that controls cell-fate decisions during development of the nervous system, has been linked to AD because it is a substrate for the
gamma-secretase enzyme activity that involves the
presenilin-1 (PS1)
protein in which mutations cause early-onset inherited AD. The actions of Notch can be antagonized by Numb, an evolutionarily conserved
protein that exists in four
isoforms that differ in two functional domains: a
phosphotyrosine-binding (PTB) domain and a
proline-rich region (PRR). We now report that Numb
isoforms containing a short PTB domain increase the vulnerability of PC12 cells to death induced by Abeta1-42 and by
4-hydroxynonenal, a lipid peroxidation product previously shown to mediate neurotoxic effects of Abeta. Dysregulation of cellular
calcium homeostasis occurs in cells expressing Numb
isoforms with a short PTB domain, and the death-promoting effect of Numb is abolished by pharmacological inhibition of
calcium release. The levels of Numb are increased in cultured primary hippocampal neurons exposed to Abeta, suggesting a role for endogenous Numb in the neuronal death process. Furthermore, higher levels of Numb were detected in the cortex of mice expressing mutant
amyloid precursor
protein (APP) relative to age-matched wild-type mice. Our data identify a novel
isoform-specific effect of Numb on neuronal life and death cell fate decisions potentially relevant to the pathogenesis of AD. Our findings also suggest that the effects of Numb on cell fate decisions, both during development of the nervous system and in neurodegenertive disorders, are mediated by changes in cellular
calcium homeostasis.