Calcium hypothesis of Alzheimer’s disease
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca2+ signaling pathways responsible for cognition. Hydrolysis of the β-amyloid precursor protein (APP) yields two products that can influence Ca2+ signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca2+ that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca2+ within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca2+ being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca2+ signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca2+ signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca2+-dependent protein phosphatase calcineurin. The alteration in Ca2+ signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.
KeywordsInositol 1,4,5-trisphosphate Aging AMPA receptor Memory Ca2+ mobilization Ca2+ stores Synaptic plasticity Calcineurin Calbindin Calcium signaling
Note added in proof
Two very recent reports have identified new AD susceptibility genes (CLU, CR1 and PICALM) [57, 58], which provide further support for the hypotheses outlined in this review. CLU encodes the protein clustrin, which function like ApoE (see Fig. 2) to bind soluble amyloids to regulate their toxicity [57, 58]. CR1 is the gene for the complement component (3b/4b) receptor 1, which functions in the complement system to clear soluble amyloids . PICALM encodes a phosphatidylinositol-binding clathrin assembly protein, which is located in pre- and post-synaptic neuronal endings where it plays a role in clathrin-mediated endocytosis . The genetic modifications to PICALM may function to divert APP to the late endosomes to promote the formation of soluble amyloids (see step 4 in Figure 2). In addition, mutated PICALM may contribute to the decline in synaptic plasticity seen in AD by increasing the rate of endocytosis. Such an action would thus mirror the effect of elevated Ca2+ by enhancing the process of long-term depression (LTD), which might be one of the major defects responsible for early memory loss in AD.
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