4.4
PresenilinsMutations in presenilin 1 (PS1) and presenilin 2 (PS2) have been linked to inherited
forms of early onset Alzheimer’s disease (AD). AD is caused by degeneration of cortical
and limbic neurons of the brain, and is characterized by neurofibrillary tangles and
extracellular aggregates or plaques of amyloid β peptide (Aβ), a processed fragment
of the amyloid precursor protein (APP) (Hardy, 1997). Aβ induces synaptic
dysfunction and neuronal apoptosis in experimental models by generating oxidative
stress and disruption of ion homeostasis through lipid peroxidation (Mattson, 2000).
The molecular mechanism by which presenilin mutations lead to AD seems to involve
both increased production of the toxic Aβ peptide and sensitization of neurons to
apoptosis. For example, PS1 has been shown to regulate the γ-secretase activity that
is required to generate Aβ, and dominant mutations in PS1 and PS2, cause altered
processing of APP and generate Aβ (Mattson et al., 2001). In addition, neurons or
transgenic mice expressing presenilin mutants are more sensitive to excitotoxicity and
neuronal apoptosis induced by trophic factor withdrawal or exposure to Aβ, itself
(Mattson et al., 2001).
PS1 and PS2 are widely expressed and highly homologous integral membrane
proteins of the ER containing eight predicted transmembrane domains with the N-
terminus, C-terminus, and a hydrophilic loop between transmembrane domains 6
and 7 facing the cytoplasm. Presenilins have been reported to bind a number of ER
Ca2+ regulatory proteins, including the RyR and its associated protein, sorcin, and
the Ca2+-binding proteins calsenilin and calmyin (Mattson et al., 2001). Several lines
of evidence suggest that the phenotype conferred by presenilin mutants may be the
result of ER Ca2+ imbalances. Expression of presenilin mutants increases ER Ca2+
stores, resulting in greater elevations in [Ca2+]c after IP 3 R/RyR stimulation (Guo et
al., 1996; Wolozin et al., 1996). Overexpression of Ca2+-binding proteins, chelating
cytosolic Ca2+, or pharmacologically inhibiting IP 3 R—or RyR Ca2+-release channels
inhibits the toxic effects of PS1 mutations (Mattson et al., 2001). The increased release
of ER Ca2+ caused by presenilin mutants may promote capacitative Ca2+ entry
through plasma membrane voltage-dependent Ca2+ channels, leading to global
perturbations in Ca2+ homeostasis. Importantly, sustained elevations in intracellular
Ca2+ are strongly implicated in the pathogenesis of AD (Mattson et al., 2001). In
addition, several reports indicate that APP processing is regulated by intracellular Ca^2
- levels, suggesting that presenilin mutants indirectly promote Aβ production by their
effects on Ca2+ (Querfurth and Selkoe, 1994; Li et al., 1995; Mattson et al., 2001;
Sennvik et al., 2001). Of note, PS1 and PS2 are both cleaved by caspase-3 within the
large cytosolic loop, an effect that might contribute to the apoptotic process through
Ca2+ mobilization or by some other means (Wellington and Hayden, 2000).
Cells expressing PS1 mutants found in AD patients are defective in generating a
UPR, apparently because they fail to activate Irel, PERK, and ATF-6 (Imaizumi et
al., 2001). These observations could relate to the ability of mutant PS1 to perturb
ER Ca2+ levels, and thus alter the protein-folding environment of the lumen, or to a
THE ROLE OF THE ENDOPLASMIC RETICULUM IN APOPTOSIS 117