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

• DOI: 10.1016/j.neurobiolaging.2017.06.015
• Publication Date: 2017-06-24T09:00:45Z
• Authors: Xavier Toussay; Jean-Luc Morel; Nathalie Biendon; Lolita Rotureau; François-Pierre L...; Marie-Charlotte B...; Yoon H. Cho; Nathalie Macrez
• Keywords: Male; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Gene Expression; Mice, Transgenic; Muscle, Smooth, Vascular; Sarcoplasmic Reticulum Calcium-Transporting ATPases; 03 medical and health sciences; Alzheimer Disease; Caffeine; Presenilin-1; Animals; Calcium Signaling; 0303 health sciences; [SCCO.NEUR]Cognitive science/Neuroscience; [SDV.BA]Life Sciences [q-bio]/Animal biology; Calcium-Binding Proteins; Ryanodine Receptor Calcium Release Channel; [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences; Cerebral Arteries; 3. Good health; Mice, Inbred C57BL; Mutation; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Calcium; Muscle Contraction

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.