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

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.

• Autores: Villegas Lanau, Carlos Andres; Lopera Restrepo, Francisco Javier; Sepúlveda Fallad, Diego; Barrera Ocampo, Alvaro Andrés; Hagel, Christian; Korwitz, Anne; Vinueza Veloz, María Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velázquez Pérez, Luis; Rodríguez Labrada, Roberto; Ferrer, Isidro; Langer, Thomas; De Zeeuw, Chris I.; Glatzel, Markus
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2014
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/47818
• Acceso en línea: https://hdl.handle.net/10495/47818
• Palabra clave: 610 - Medicina y salud; Enfermedad de Alzheimer; Alzheimer Disease; Sustitución de AminoácidosEspañol; Amino Acid Substitution; Calcio - metabolismo; Calcium - metabolism; Genes Dominantes; Genes, Dominant; Modelos Neurológicos; Models, Neurological; Mutación Missense; Mutation, Missense; Presenilina-1; Presenilin-1; Células de Purkinje; Purkinje Cells; Ratones Endogámicos C57BL; Mice, Inbred C57BL; Ratones Mutantes; Mice, Mutant Strains; https://id.nlm.nih.gov/mesh/D000544; https://id.nlm.nih.gov/mesh/D019943; https://id.nlm.nih.gov/mesh/D002118; https://id.nlm.nih.gov/mesh/D005799; https://id.nlm.nih.gov/mesh/D008959; https://id.nlm.nih.gov/mesh/D020125; https://id.nlm.nih.gov/mesh/D053764; https://id.nlm.nih.gov/mesh/D011689; https://id.nlm.nih.gov/mesh/D008810; https://id.nlm.nih.gov/mesh/D008817; ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc-sa/4.0/