Background. Alzheimer's disease (AD) is one of the major causes of memory loss in aging population. Mutations in presenilins result in familial Alzheimer’s disease (FAD). These mutations affect gamma-secretase function of presenilins and influence Ab42/Ab40 ratio. Our previous studies suggested that FAD mutations also affect endoplasmic reticulum (ER) calcium (Ca2+) function of presenilins and result in ER Ca2+ overload (Tu at al, 2006. Cell 126, 981-993; Zhang at al. 2010. J Neurosci 30, 8566-8580). However, mechanistic connection between ER Ca2+ signaling dysregulation and synaptic loss in AD has not been previously established.
Methods. Perform studies of Ca2+ signaling and synaptic loss in hippocampal neurons from presenilin 1 (PS1) M146V knockin (KI) model of FAD. Our approach is centered on measurements of synaptic Ca2+ signals and analysis of postsynaptic spine shapes in wild type and PS1-M146V KI neurons.
Results: In the current study we discovered that PS1-M146V KI neurons compensate for ER calcium overload by downregulating STIM2 protein, a master regulator of neuronal store operated calcium entry pathway (nSOC). We further demonstrated that similar downregulation of STIM2 occurs as a result of normal aging process. In experiments with STIM2 conditional knockout mice we demonstrate that knockout of STIM2 results in destabilization of mushroom spines in hippocampal neurons. We further demonstrate that overexpression of STIM2 results in rescue of mushroom spine deficiency in PS1-M146V KI hippocampal neurons. We determined that synaptic CaMKII acts downstream of nSOC in spines.
Conclusions. We concluded that (1) STIM2-nSOC-CaMKII pathway is essential for long-term maintenance of mushroom spines; (2) function of this pathway is compromised in aging and AD neurons due to downregulation of STIM2 expression. Our results have wide implications for basic synaptic biology and for our understanding and treatment of aging-related memory decline and AD. We further proposed that STIM2 and synaptic nSOC channels constitute a novel therapeutic targets for prevention of synaptic loss in aging and AD.