By Will Boggs, MD

WESTPORT, CT (Reuters Health) - Mutations in presenilin genes PS1 and PS2 attenuate capacitative calcium entry in neurons, leading to increased accumulation of amyloid beta peptide in familial Alzheimer's disease, according to a report in the September issue of Neuron.

Dr. Tae-wan Kim, of Columbia University, New York, and colleagues explain that capacitative calcium entry (CCE) describes the process of replenishing stores of calcium ions in the endoplasmic reticulum through plasma membrane channels.

Presenilin mutations were previously associated with impaired capacitative calcium entry in fibroblasts from patients with familial Alzheimer's disease, and the researchers therefore examined the function of PS1 and PS2 in modulating this mechanism in neurons.

Neuronal cell cultures from PS1 knockout mice showed "hyperactivated" capacitative calcium entry, the authors report, as did cell lines expressing biologically inactive PS1. However, mutations in PS1 and PS2 that are associated with familial Alzheimer's disease "universally downregulate CCE in multiple cell types, including neurons."

The researchers also found that inhibition of capacitative calcium entry "selectively increased the amyloidogenic amyloid beta peptide (A-beta-42)." A-beta-42 accumulation, in contrast, had no effect on capacitative calcium entry.

"Reduced CCE is most likely an early cellular event leading to increased A-beta-42 generation associated with [familial Alzheimer's disease] mutant presenilins," the authors conclude.

"In summary, we found a novel therapeutic target of Alzheimer's disease at the molecular level," Dr. Kim commented to Reuters Health. "We believe that selective activators of the CCE pathway (including agonists of the relevant CCE channel) can be employed to reduce the levels of the toxic peptide A-beta-42 that plays a causative role in AD."

That avenue is being explored, Dr. Kim indicated. "In collaboration with Neurogenetics, Inc., a San Diego-based biopharmaceutical company, we are currently screening for compounds which can modulate CCE."

(From Reuters Health)