Alzheimer’s disease (AD) is the most common reason for elderly dementia, its prevalence will continue to increase with aging population of the world. Therefore, the search of effective AD cure meets urgent need. In our recent breakthrough study we observed that reduced postsynaptic neuronal store-operated calcium entry (nSOC) is responsible for mushroom spine loss in knock-in mice expressing mutant human presenilin 1 (PS1-M146V-KI) (Sun at al (2014) Neuron. 82:79-93). We have shown that key player of SOC STIM2 but not STIM1 is downregulated in the hippocampus of PS1-KI mice. Moreover, we have demonstrated that hyperexpression of STIM2 protein rescues synaptic nSOC and mushroom spine loss in PS1-KI hippocampal neurons (Sun at al (2014) Neuron. 82:79-93). However, PS1-M146V-KI mice do not express human amyloid precursor protein (APP) and do not form Ab40 and Ab42 – the main constitute of amyloid hypothesis of AD. Since amyloid hypothesis is still considered to be dominant the next question arises: does similar pathological STIM2-nSOC process take place in conditions of amyloid toxicity? At the current study we have developed in vitro and in vivo models of low amyloid synaptotoxicity. We were particularly interested in finding of low amyloid synaptotoxicity conditions since we believe it correlates best with the early stages of AD. Application of pharmaceutical drugs at early stages of the disease will be most effective. In our studies we observed decrease in STIM2 protein levels in both in vitro and in vivo models of amyloid synaptotoxicity. Moreover, in in vitro conditions we detected reduction of mushroom spine numbers. Our results suggest that downregulation of STIM2-nSOC pathway may play a general role in AD-related synaptic pathology and that modulators/activators of nSOC may be considered as potential therapeutic agents for treatment of AD patients.
This work was supported by the contract with the Russian Ministry of Science 11.G34.31.0056 (Ilya Bezprozvanny) and by the grant from private foundation “Dynasty” DP-B-11-14 (Elena Popugaeva).