ER calcium and Alzheimer's disease: in a state of flux

Abstract

The calcium ion (Ca(2+)) plays fundamental roles in orchestrating dynamic changes in the function and structure of nerve cell circuits in the brain. The endoplasmic reticulum (ER), an organelle that actively removes Ca(2+) from the cytoplasm, can release stored Ca(2+) through ER membrane receptor channels responsive either to the lipid messenger inositol trisphosphate (IP(3)) or to cytosolic Ca(2+). Emerging findings suggest that perturbed ER Ca(2+) homeostasis contributes to the dysfunction and degeneration of neurons that occurs in Alzheimer's disease (AD). Presenilin-1 (PS1) is an integral membrane protein in the ER; mutations in PS1 that cause early-onset inherited AD increase the pool of ER Ca(2+) available for release and also enhance Ca(2+) release through ER IP(3)- and ryanodine-sensitive channels. By enhancing Ca(2+) flux across the ER membrane, PS1 mutations may exaggerate Ca(2+) signaling in synaptic terminals and thereby render them vulnerable to dysfunction and degeneration in the settings of aging and amyloid accumulation in AD.

Figure 1

Mechanisms that regulate synaptic calcium dynamics, and their possible roles in the pathogenesis of Alzheimer’s disease (AD). A. The endoplasmic reticulum (ER) is present in both presynaptic axon terminals (left) and postsynaptic dendrites (right) where it regulates Ca²⁺-mediated processes involved in synaptic transmission and structural plasticity. In response to membrane depolarization, Ca²⁺ enters presynaptic terminals through voltage-dependent Ca²⁺ channels (VDCC) and N-methyl-D-aspartate (NMDA) glutamate receptors. The elevated cytosolic Ca²⁺ then triggers Ca²⁺ release through ryanodine receptors (RyR), and Ca²⁺ may also be released through IP₃ receptors (IP₃R) in response to activation of metabotropic receptors (R). The elevated Ca²⁺ concentration in the cytosol triggers fusion of glutamate-containing synaptic vesicles with the synaptic plasma membrane resulting in release of glutamate into the synaptic cleft. The β-amyloid precursor protein (APP) is present in the presynaptic membrane, where it can be proteolytically processed to release the amyloid β-peptide (Aβ). Aβ then self-aggregates on pre- and post-synaptic membranes where it causes oxidative stress and membrane lipid peroxidation which can disrupt cellular Ca²⁺ homeostasis. Glutamate binds postsynaptic AMPA receptors resulting in sodium influx, membrane depolarization and calcium influx through NMDA receptors and VDCC. Glutamate also binds metabotropic receptors (mGluR) coupled to the GTP-binding protein Gq which then activates phospholipase C (PLC) resulting in generation of IP₃. SERCA, sarco- (smooth-) endoplasmic reticulum Ca²⁺-ATPase. AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor). B. Presenilin-1 (PS1) is an integral membrane protein that may modulate ER Ca²⁺ dynamics, thereby playing roles in synaptic plasticity and the pathogenesis of AD. PS1 can interact with IP₃R and RyR, and mutations in PS1 that cause early-onset inherited AD enhance the amount of Ca²⁺ released in response to IP₃ or Ca²⁺ influx. PS1 may itself function as a Ca²⁺ leak channel and PS1 mutations may compromise this function of PS1 resulting in an increased intraluminal Ca²⁺ concentration.

Figure 1

Mechanisms that regulate synaptic calcium dynamics, and their possible roles in the pathogenesis of Alzheimer’s disease (AD). A. The endoplasmic reticulum (ER) is present in both presynaptic axon terminals (left) and postsynaptic dendrites (right) where it regulates Ca²⁺-mediated processes involved in synaptic transmission and structural plasticity. In response to membrane depolarization, Ca²⁺ enters presynaptic terminals through voltage-dependent Ca²⁺ channels (VDCC) and N-methyl-D-aspartate (NMDA) glutamate receptors. The elevated cytosolic Ca²⁺ then triggers Ca²⁺ release through ryanodine receptors (RyR), and Ca²⁺ may also be released through IP₃ receptors (IP₃R) in response to activation of metabotropic receptors (R). The elevated Ca²⁺ concentration in the cytosol triggers fusion of glutamate-containing synaptic vesicles with the synaptic plasma membrane resulting in release of glutamate into the synaptic cleft. The β-amyloid precursor protein (APP) is present in the presynaptic membrane, where it can be proteolytically processed to release the amyloid β-peptide (Aβ). Aβ then self-aggregates on pre- and post-synaptic membranes where it causes oxidative stress and membrane lipid peroxidation which can disrupt cellular Ca²⁺ homeostasis. Glutamate binds postsynaptic AMPA receptors resulting in sodium influx, membrane depolarization and calcium influx through NMDA receptors and VDCC. Glutamate also binds metabotropic receptors (mGluR) coupled to the GTP-binding protein Gq which then activates phospholipase C (PLC) resulting in generation of IP₃. SERCA, sarco- (smooth-) endoplasmic reticulum Ca²⁺-ATPase. AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor). B. Presenilin-1 (PS1) is an integral membrane protein that may modulate ER Ca²⁺ dynamics, thereby playing roles in synaptic plasticity and the pathogenesis of AD. PS1 can interact with IP₃R and RyR, and mutations in PS1 that cause early-onset inherited AD enhance the amount of Ca²⁺ released in response to IP₃ or Ca²⁺ influx. PS1 may itself function as a Ca²⁺ leak channel and PS1 mutations may compromise this function of PS1 resulting in an increased intraluminal Ca²⁺ concentration.