Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis
Open accessAbstract
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 af…
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Previous studies of our group have identified molecular differences between SAD and FAD in addition to divergences in clinical manifestations.
“Previous studies of our group have identified molecular differences between SAD and FAD [55, 56, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] in addition to divergences in the clinical manifestations [55, 56].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [74]
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- Authors
- Sepulveda-Falla, D., Barrera-Ocampo, A., Hagel, C., Korwitz, A., Vinueza-Veloz, M. F., Zhou, K., Schonewille, M., Zhou, H., Velazquez-Perez, L., Rodriguez-Labrada, R., Villegas, A., Ferrer, I., Lopera, F., Langer, T., De Zeeuw, C. I., & Glatzel, M.
- Affiliations
- University of Cologne (DE)
- Erasmus MC (NL)
- Royal Netherlands Academy of Arts and Sciences (NL)
- Universidad de Antioquia (CO)
- Corresponding author
- Glatzel, Markus
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-02-24
- Volume
- 124
- Issue
- 4
- Pages
- 1552-1567
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3973081
- OpenAlex
- W1983492081
- Cited by
- 135
- References
- 8
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 13 · 2023: 12 · 2022: 10 · 2021: 16 · 2020: 18 · 2019: 11 · 2018: 6 · 2017: 10 · 2016: 12 · 2015: 8 · 2014: 3
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Institutional Repository University of Antioquia (University of Antioquia) (submittedVersion, cc-by-nc-sa)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- familial Alzheimer's disease, presenilin 1, cerebellar dysfunction, Purkinje cells, calcium homeostasis, mitochondrial dysfunction, ER-mitochondria tethering, IP3 receptor, CACNA1A, Miro1, KIF5C, cerebellar ataxia, amyloid plaques
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Calcium, Cell Line, Cerebellum, Disease Models, Animal, Endoplasmic Reticulum, Female, Genes, Dominant, Heterozygote, Homeostasis, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Middle Aged, Mitochondria, Models, Neurological, Purkinje Cells, Case-Control Studies, Amyloid beta-Protein Precursor, Amino Acid Substitution, Mutation, Missense, Mice, Presenilin-1
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