The presenilins

Presenilin-1 and presenilin-2 are highly homologous genes located on chromosomes 14 and 1, respectively, that have recently been linked to some cases of early-onset autosomal dominant inherited forms of Alzheimer's disease (AD). Presenilins are integral membrane proteins localized in the endoplasmic reticulum of neurons throughout the nervous system. Studies of presenilin-1 knockout mice, and of invertebrate homologues of presenilins and their interacting proteins, suggest major roles for presenilins in normal development. Presenilin-1 mutant knockin mice do not exhibit developmental abnormalities, which indicates that the pathogenic mechanism of presenilin mutations involves gain of an adverse property of the mutant protein. Expression of presenilin mutations in cultured neurons and transgenic mice results in increased sensitivity to apoptosis induced by trophic factor withdrawal and exposure to oxidative and metabolic insults, and also alters gene expression. The pathogenic mechanism of presenilin mutations may involve perturbed endoplasmic reticulum calcium homeostasis resulting in enhanced oxidative stress, altered proteolytic processing of the amyloid precursor protein (APP), and increased neuronal vulnerability to excitotoxicity. Studies of presenilins are rapidly increasing our understanding the molecular and cellular underpinnings of AD and are also elucidating novel roles of the endoplasmic reticulum in neuronal plasticity and cell death.