Title:
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Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis
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Author:
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Sepulveda Falla, Diego; Barrera Ocampo, Alvaro; Hagel, Christian; Korwitz, Anne; Vinueza Veloz, María Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velázquez Pérez, Luis; Rodríguez Labrada, Roberto; Villegas, Andrés; Ferrer, Isidro (Ferrer Abizanda); Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I.; Glatzel, Markus
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Abstract:
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Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration. |
Subject(s):
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-Malaltia d'Alzheimer -Homeòstasi -Cervell -Alzheimer's disease -Homeostasis -Brain |
Rights:
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(c) American Society for Clinical Investigation, 2014
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Document type:
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Article Article - Published version |
Published by:
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American Society for Clinical Investigation
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