Ca2+ dysregulation in neurons from transgenic mice expressing mutant presenilin 2.
Mutations in amyloid precursor protein (APP), and presenilin-1 and presenilin-2 (PS1 and PS2) have causally been implicated in Familial Alzheimer's Disease (FAD), but the mechanistic link between the mutations and the early onset of neurodegeneration is still debated. Although no consensus has yet been reached, most data suggest that both FAD-linked PS mutants and endogenous PSs are involved in cellular Ca2+ homeostasis. We here investigated subcellular Ca2+ handling in primary neuronal cultures and acute brain slices from wild type and transgenic mice carrying the FAD-linked PS2-N141I mutation, either alone or in the presence of the APP Swedish mutation. Compared with wild type, both types of transgenic neurons show a similar reduction in endoplasmic reticulum (ER) Ca2+ content and decreased response to metabotropic agonists, albeit increased Ca2+ release induced by caffeine. In both transgenic neurons, we also observed a higher ER-mitochondria juxtaposition that favors increased mitochondrial Ca2+ uptake upon ER Ca2+ release. A model is described that integrates into a unifying hypothesis the contradictory effects on Ca2+ homeostasis of different PS mutations and points to the relevance of these findings in neurodegeneration and aging.
Department of Biomedical Sciences, University of Padua, Padua, Italy.
Maulilio J
MJ
Kipanyula
Laura
L
Contreras
Enrico
E
Zampese
Cristian
C
Lazzari
Andrea K C
AK
Wong
Paola
P
Pizzo
Cristina
C
Fasolato
Tullio
T
Pozzan
D000544:Alzheimer Disease; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D053766:Presenilin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012433:Ryanodine / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D053766:Presenilin-2; D012433:Ryanodine; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium