SFN: Calcium Signaling and Alzheimer's

Presenilins, neuronal calcium signaling, and Alzheimer's disease. Presented by I. BEZPROZVANNY from UT Southwestern Med. Ctr. Dallas. This talk was part of the New Advances in Calcium Signaling in Neuronal Function and Disease Symposium. The initial question proposed by the speaker is how mutations in presenilins (PS-FAD mutations) cause excessive calcium release from the ER. They hypothesize that presenilins function as ER calcium leak channels. Mutations disrupt ER calcium leak function and result in overfilled calcium stores. Loss of function for presenilin ER calcium leak becomes gain of function.

Normally, presenilins act in homeostasis of ER calcium stores. In the KO cells, this homeostasis is disrupted, so that ER calcium stores are overfilled, and when ER calcium stores are released, a much greater concentration of calcium is released.

The initial discovery and analysis of ER calcium leak function of presenilins was based on bilayer recordings of recombinant proteins and on calcium imaging experiments with PS DKO mouse embryonic fibroblasts. One question the investigators had was whether presenilins function as neuronal ER calcium leak channels. The answer is yet – recordings (and imaging) from neurons in their presenilin-KO mouse show a 2-3 fold increases in ER calcium pools as compared to wild type neurons.

So with evidence that presnilins are neuronal ER calcium leak channels, they next wondered how neurons compensate for the lack of presenilins. They found a increase in the Ryan receptor in neurons lacking presenilins – implying that the RyanR is involved in homeostatic compensation. Mice lacking RyanRs display a significant increase in the calcium pool. Combination of the presenilin and RyanR KO shows a 15-20 fold increase in the size of the ER calcium pool – significantly enhanced compared to the 2-3 fold increases in calcium pool size that result in the individual presinilin or RyanR KO conditions.

This suggests a model where both presinilin and RyanR are involved in homeostasis of ER calcium stores. Removing one of these mechanisms shifts the load to the other mechanism. However, removal of both mechanisms results in breakdown of ER calcium pool homeostasis, leading to apoptosis and accumulation of amyloid plaques typical of Alzheimer’s.

The speaker notes that loss of ER calcium leak channel homeostasis is not the only determinant of familiar Alzheimer’s – there are several other identified mutations. So the question is, given these multiple mechanisms, is there a downstream mechanism that they all affect, disruption of which results in Alzheimers. He hypothesizes that the identified mutations that underlie familial Alzheimer’s share a tendency towards network hyperexcitability. He proposes that mutations in presinilin cause disruption of ER calcium levels (via altering levels of AB42/40), disrupting neuronal hyperexcitability, which in turn activated a positive feedback loop that ends up further increasing ER calcium stores via up-regulation of AB42/40. Note: the speaker presented a more complex picture of the protein mechanisms behind this loop, further describing a second loop that he proposes to be initiated by hyperexcitability, but spoke too fast for me to note down the specifics.

So how does this relate to aging neurons (due to the link between Alzheimers and advanced age)? He notes that aging neurons are known to have increased levels of internal calcium, and perhaps this tendency is able to initiate the multiple feedback loops he proposed.