| Alzheimer's disease (AD) is the most common age-associated debilitating neurodegenerative disorder, characterized by progressive decline in cognitive and functional abilities. Increasing evidence suggests that cerebral elevation and accumulation of the amyloid beta-peptide (Abeta) are early and necessary steps in AD pathogenesis. Abeta is produced by sequential proteolytic cleavages of the amyloid precursor protein (APP) by a set of proteases termed beta- and gamma-secretases. Mutations in the genes encoding the presenilins are the most common cause of early-onset familial Alzheimer's disease (FAD). Although FAD accounts for ∼5% of AD cases, at the neuropathological level it is phenotypically indistinguishable from the more common, sporadic form of AD. Thus, understanding the genotype-to-phenotype transition in FAD is likely to shed light on the pathogenesis of sporadic AD. Presenilins serve as the catalytical components of the gamma-secretase, and FAD mutations lead to increase in the levels of Abeta42, a more amyloidogenic form of Abeta, considered to be a key pathogenic agent in AD. Increasing evidence indicates that presenilins are involved in additional cellular functions, unrelated to their role in the proteolytic activity of the y-secretase. Two of the most consistent FAD-associated cellular phenotypes include ion channel dysfunction and membrane trafficking defects. However, the relationship between the proteolytic function of the presenilins and presenilin-dependent regulation of ion entry remains unknown. We find that TRPM7-associated Mg2+-inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells and the observed channel deficits are restored by addition of phosphatidylinositol 4,5-bisphosphate (PIP2), a known regulator of MIC/TRPM7 channels. Lipid analyses show that PIP2 turnover is selectively affected in FAD mutant presenilins cells. We also find that modulation of cellular PIP2 closely correlates with Abeta42 levels and cell-surface targeting of APP. Our data suggest that PIP2 imbalance may contribute to AD pathogenesis by affecting multiple cellular pathways, such as the generation of toxic Abeta42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP2 may offer a novel therapeutic approach in AD. |
