Presenilins, the Endoplasmic Reticulum, and Neuronal Apoptosis in Alzheimer's Disease

Abstract

Many cases of autosomal dominant inherited forms of early‐onset Alzheimer's disease are caused by mutations in the genes encoding presenilin‐1 (PS‐1; chromosome 14) and presenilin‐2 (PS‐2; chromosome 1). PSs are expressed in neurons throughout the brain wherein they appear to be localized primarily to the endoplasmic reticulum (ER) of cell bodies and dendrities. PS‐1 and PS‐2 show high homology and are predicted to have eight transmembrane domains with the C terminus, N terminus, and a loop domain all on the cytosolic side of the membrane; an enzymatic cleavage of PSs occurs at a site near the loop domain. The normal function of PSs is unknown, but data suggest roles in membrane trafficking, amyloid precursor protein processing, and regulation of ER calcium homeostasis. Homology of PSs to the C. elegans gene sel‐12, which is involved in Notch signaling, and phenotypic similarities of PS‐1 and Notch knockout mice suggest a developmental role for PSs in the nervous system. When expressed in cultured cells and transgenic mice, mutant PSs promote increased production of a long form of amyloid β‐peptide (Aβ1‐42) that may possess enhanced amyloidogenic and neurotoxic properties. PS mutations sensitize cultured neural cells to apoptosis induced by trophic factor withdrawal, metabolic insults, and amyloid β‐peptide. The mechanism responsible for the proapoptotic action of mutant PSs may involve perturbed calcium release from ER stores and increased levels of oxidative stress. Recent studies of apoptosis in many different cell types suggest that ER calcium signaling can modulate apoptosis. The evolving picture of PS roles in neuronal plasticity and Alzheimer's disease is bringing to the forefront the ER, an organelle increasingly recognized as a key regulator of neuronal plasticity and survival.

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

“…The lipoperoxidation process could influence the pathogenesis of AD [55,59]. Indeed, 4-hydroxynonenal (4-HNE), which is one of the most reactive end products of lipoperoxidation, appears to induce neuronal death upon binding to proteins by altering important transporter proteins, such as the ATPases involved in calcium homeostasis and the glutamate transporter EAAT2 [10,52]. The healthy brain is protected from oxidative injury by antioxidant defences that include antioxidant enzymes and free radical scavengers.…”

Reduction in CHT1-mediated choline uptake in primary neurons from presenilin-1 M146V mutant knock-in mice

“…Mounting evidence suggests that aberrant production and aggregation of the neurotoxic amyloid β-peptide 1-42 (Aβ42) play a key role in the pathogenesis of Alzheimer's disease. Mutations in presenilins have been shown to significantly increase the production of Aβ42 (Annaert et al, 1999;Borchelt et al, 1997;Cai et al, 2006;Capell et al, 2000;Chui et al, 1999;Duff et al, 1996;Guo et al, 1996;Guo et al, 1997;Guo et al, 1998;Guo et al, 1999c;Mattson et al, 1998;Scheuner et al, 1996). Of importance, a recent report found that, in freely moving PDAPP mice (a well-characterized transgenic mouse model of AD), Aβ42 formed a complex with CHT1 in co-immunoprecipitation assays, which may impair steadystate and on-demand ACh release (Bales et al, 2006).…”

“…Mutations in presenilin-1 (PS-1) are responsible for majority of early onset familial AD, and have been shown to be involved in regulation of neuronal apoptosis and aberrant production and aggregation of amyloid β-peptide (Annaert et al, 1999;Borchelt et al, 1997;Cai et al, 2006;Capell et al, 2000;Chui et al, 1999;Duff et al, 1996;Guo et al, 1996;Guo et al, 1997;Guo et al, 1998;Guo et al, 1999c;Mattson et al, 1998;Scheuner et al, 1996). Mutations in presenilins have also been shown to regulate cholinergic signaling, although the precise roles of these mutations in in vitro and in vivo models of AD are still unsettled (De Sarno et al, 2001;Hartmann et al, 2004;Hernandez et al, 2001;Mattson et al, 1998;Pedersen et al, 1997;Vaucher et al, 2002).…”

“…Mutations in presenilins have also been shown to regulate cholinergic signaling, although the precise roles of these mutations in in vitro and in vivo models of AD are still unsettled (De Sarno et al, 2001;Hartmann et al, 2004;Hernandez et al, 2001;Mattson et al, 1998;Pedersen et al, 1997;Vaucher et al, 2002). Using gene targeting and expression protocols, we previously generated and characterized presenilin-1 mutant M146V knock-in (PS-1 M146V KI) mice and found an increased vulnerability of neurons from these mice to insults relevant to the pathogenesis of AD (Guo et al, 1999a;Guo et al, 1999b;Guo et al, 1999c).…”

Involvement of Gadd153 in the pathogenic action of presenilin‐1 mutations

“…Whereas most cases of AD are not caused by a specific genetic defect and have a late age of onset, some cases are characterized by an early age of onset and a dominant inheritance pattern. Mutations in the gene encoding presenilin-1 (PS1) on chromosome 14 are responsible for many cases of inherited AD (Hardy 1997;Mattson et al 1998). PS1 is an integral membrane protein expressed in neurons throughout the brain where it is localized primarily in the endoplasmic reticulum (ER).…”