Research ArticleAlzheimer’s Disease

Gain-of-Function Enhancement of IP3 Receptor Modal Gating by Familial Alzheimer’s Disease–Linked Presenilin Mutants in Human Cells and Mouse Neurons

See allHide authors and affiliations

Science Signaling  23 Mar 2010:
Vol. 3, Issue 114, pp. ra22
DOI: 10.1126/scisignal.2000818

You are currently viewing the editor's summary.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Opening the Calcium Floodgates?

Alzheimer’s disease (AD), which is the most common cause of dementia, is a neurodegenerative disorder that affects some 5 million Americans. Although most cases of AD are sporadic, an early-onset form of familial AD (FAD) has been linked to mutations in the presenilins (PSs), transmembrane proteins localized to the endoplasmic reticulum (ER). Cheung et al. investigated the effects of wild-type and mutant forms of PS on inositol trisphosphate receptor (IP3R)–mediated Ca2+ release from the ER in various different cellular systems, including human lymphoblasts derived from individuals with FAD and cortical neurons from a mouse model of FAD. They found that FAD-linked PS mutants enhanced Ca2+ release by modulating IP3R channel gating through a gain-of-function mechanism, consistent with the autosomal-dominant inheritance of FAD. FAD-linked PS mutants, but not PS mutants associated with another form of dementia, shifted IP3R channel gating to a mode in which the probability that individual channels were open after stimulation was increased, leading to exaggerated Ca2+ signals.

View Full Text

Stay Connected to Science Signaling