1. Familial Alzheimer’s disease presenilin-2 mutants affect Ca2+ homeostasis and brain network excitability
- Author
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Nelly Redolfi, Paola Pizzo, Diana Pendin, Elisa Greotti, Alessandro Leparulo, Cristina Fasolato, Tullio Pozzan, Elena Scremin, Riccardo Filadi, Chiara Gomiero, Emy Basso, Luisa Galla, and Nicola Vajente
- Subjects
Aging ,Amyloid beta ,Cell ,Mutant ,Presenilin ,Alzheimer’s disease ,Amyloid-beta ,Brain network ,Ca2+ probes ,Calcium homeostasis ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,Amyloid precursor protein ,Dementia ,030212 general & internal medicine ,biology ,Neurodegeneration ,medicine.disease ,medicine.anatomical_structure ,biology.protein ,Geriatrics and Gerontology ,Age of onset ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly. Few cases are familial (FAD), due to autosomal dominant mutations in presenilin-1 (PS1), presenilin-2 (PS2) or amyloid precursor protein (APP). The three proteins are involved in the generation of amyloid-beta (Aβ) peptides, providing genetic support to the hypothesis of Aβ pathogenicity. However, clinical trials focused on the Aβ pathway failed in their attempt to modify disease progression, suggesting the existence of additional pathogenic mechanisms. Ca2+ dysregulation is a feature of cerebral aging, with an increased frequency and anticipated age of onset in several forms of neurodegeneration, including AD. Interestingly, FAD-linked PS1 and PS2 mutants alter multiple key cellular pathways, including Ca2+ signaling. By generating novel tools for measuring Ca2+ in living cells, and combining different approaches, we showed that FAD-linked PS2 mutants significantly alter cell Ca2+ signaling and brain network activity, as summarized below.
- Published
- 2019