Presenilin 1 mutation decreases both calcium and contractile responses in cerebral arteries

Abstract

Mutations or upregulation in presenilin 1 (PS1) gene are found in familial early-onset Alzheimer's disease or sporadic late-onset Alzheimer's disease, respectively. PS1 has been essentially studied in neurons and its mutation was shown to alter intracellular calcium (Ca²⁺) signals. Here, we showed that PS1 is expressed in smooth muscle cells (SMCs) of mouse cerebral arteries, and we assessed the effects of the deletion of exon 9 of PS1 (PS1dE9) on Ca²⁺ signals and contractile responses of vascular SMC. Agonist-induced contraction of cerebral vessels was significantly decreased in PS1dE9 both in vivo and ex vivo. Spontaneous activity of Ca²⁺ sparks through ryanodine-sensitive channels (RyR) was unchanged, whereas the RyR-mediated Ca²⁺-release activated by caffeine was shorter in PS1dE9 SMC when compared with control. Moreover, PS1dE9 mutation decreased the caffeine-activated capacitive Ca²⁺ entry, and inhibitors of SERCA pumps reversed the effects of PS1dE9 on Ca²⁺ signals. PS1dE9 mutation also leads to the increased expression of SERCA3, phospholamban, and RyR3. These results show that PS1 plays a crucial role in the cerebrovascular system and the vascular reactivity is decreased through altered Ca²⁺ signals in PS1dE9 mutant mice.

Keywords: Alzheimer's disease; Calcium; Cerebral arteries; Contraction; Presenilin; Smooth muscle cells.