Open AccessCa 2+ dysregulation in neurons from transgenic mice expressing mutant presenilin 2
Author(s) -
Kipanyula Maulilio J.,
Contreras Laura,
Zampese Enrico,
Lazzari Cristian,
Wong Andrea K. C.,
Pizzo Paola,
Fasolato Cristina,
Pozzan Tullio
Publication year - 2012
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2012.00858.x
Subject(s) - neurodegeneration , presenilin , biology , endoplasmic reticulum , genetically modified mouse , transgene , amyloid precursor protein , mutant , mutation , microbiology and biotechnology , wild type , alzheimer's disease , genetics , medicine , disease , gene
Summary 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 Ca 2+ homeostasis. We here investigated subcellular Ca 2+ 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) Ca 2+ content and decreased response to metabotropic agonists, albeit increased Ca 2+ release induced by caffeine. In both transgenic neurons, we also observed a higher ER–mitochondria juxtaposition that favors increased mitochondrial Ca 2+ uptake upon ER Ca 2+ release. A model is described that integrates into a unifying hypothesis the contradictory effects on Ca 2+ homeostasis of different PS mutations and points to the relevance of these findings in neurodegeneration and aging.