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

• Published in: The Journal of clinical investigation Vol. 124; no. 4; pp. 1552 - 1567
• Main Authors: Sepulveda-Falla, Diego, Barrera-Ocampo, Alvaro, Hagel, Christian, Korwitz, Anne, Vinueza-Veloz, Maria Fernanda, Zhou, Kuikui, Schonewille, Martijn, Zhou, Haibo, Velazquez-Perez, Luis, Rodriguez-Labrada, Roberto, Villegas, Andres, Ferrer, Isidro, Lopera, Francisco, Langer, Thomas, De Zeeuw, Chris I., Glatzel, Markus
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2014
• Subjects: Adult; Age; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amino Acid Substitution; Amyloid beta-Protein Precursor - metabolism; Animals; Ataxia; Biomedical research; Brain; Calcium - metabolism; Calcium channels; Case-Control Studies; Cell Line; Cerebellum; Cerebellum - metabolism; Cerebellum - pathology; Cervell; Consent; Development and progression; Disease Models, Animal; Endoplasmic Reticulum - pathology; Ethics; Female; Genes, Dominant; Genetic aspects; Heterozygote; Homeostasis; Homeòstasi; Humans; Malaltia d'Alzheimer; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Middle Aged; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Models, Neurological; Mutation; Mutation, Missense; Pathology; Physiological aspects; Presenilin-1 - genetics; Presenilin-1 - metabolism; Presenilins; Purkinje Cells - metabolism; Software; Studies; Variables
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI66407

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.