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.