Desynchronizing Plasmodium Cell Cycle Increases Chloroquine Protection at Suboptimal Doses

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Ca 2+ dysregulation in neurons from transgenic mice expressing mutant presenilin 2

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. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.Peer Reviewe