Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis

D Sepulveda-Falla, A Barrera-Ocampo, C Hagel, A Korwitz, Maria Vinueza Veloz, Jackie Zhou, martijn Schonewille, Haibo Zhou, L Velazquez-Perez, R Rodriguez-Labrada, A Villegas, I Ferrer, F Lopera, T Langer, Chris de Zeeuw, M Glatzel

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Abstract

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 PSI-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar beta-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 A beta aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and A beta precursor processing, leading to FAD and neurodegeneration.
Original languageUndefined/Unknown
Pages (from-to)1552-1567
Number of pages16
JournalJournal of Clinical Investigation
Volume124
Issue number4
DOIs
Publication statusPublished - 2014

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