Exploring presenilin-1-associated familial Alzheimer's disease
Familial Alzheimer's disease (FAD) is an early on-set, hereditary form of neurological disease with variable pathophysiology that is often associated with loss of cerebellar function and amyloid plaque formation. Diego Sepulveda-Falla and colleagues investigated how a particular PS1 mutation (PS1-E280A), present in large Columbian kindred of FAD patients, promotes disease. Postmortem evaluation of cerebellar tissue from patients revealed that PS1-E280A is associated with Purkinje cell loss, an abundance of abnormal mitochondria and loss of calcium transport proteins. Furthermore, cell culture and murine models of PS1-E280A FAD revealed that PS1alterations disrupt calcium homeostasis and mitochondrial transport within cerebellar neurons, resulting in increased amyloid plaque formation and cerebellar dysfunction.
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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 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.
Authors
Diego Sepulveda-Falla, Alvaro Barrera-Ocampo, Christian Hagel, Anne Korwitz, Maria Fernanda Vinueza-Veloz, Kuikui Zhou, Martijn Schonewille, Haibo Zhou, Luis Velazquez-Perez, Roberto Rodriguez-Labrada, Andres Villegas, Isidro Ferrer, Francisco Lopera, Thomas Langer, Chris I. De Zeeuw, Markus Glatzel
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ISSN: 0021-9738 (print), 1558-8238 (online)