Familial Alzheimer’s disease presenilin-2 mutants affect Ca2+ homeostasis and brain network excitability

• Published in: Aging clinical and experimental research Vol. 33; no. 6; pp. 1705 - 1708
• Main Authors: Pendin, Diana, Fasolato, Cristina, Basso, Emy, Filadi, Riccardo, Greotti, Elisa, Galla, Luisa, Gomiero, Chiara, Leparulo, Alessandro, Redolfi, Nelly, Scremin, Elena, Vajente, Nicola, Pozzan, Tullio, Pizzo, Paola
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-06-2021; Springer Nature B.V
• Subjects: Aging; Alzheimer's disease; Brain research; Endoplasmic reticulum; Fibroblasts; Geriatrics/Gerontology; Homeostasis; Medicine; Medicine & Public Health; Metabolism; Mitochondria; Mutation; Peptides; Short Communication; Alzheimer’s disease; Presenilin; probes; Brain network; Calcium homeostasis; Ca; Amyloid-beta
• ISSN: 1720-8319; 1594-0667; 1720-8319
• DOI: 10.1007/s40520-019-01341-0

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. Ca
2+
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 Ca
2+
signaling. By generating novel tools for measuring Ca
2+
in living cells, and combining different approaches, we showed that FAD-linked PS2 mutants significantly alter cell Ca
2+
signaling and brain network activity, as summarized below.