Calcium Signaling and Mitochondrial Function in Presenilin 2 Knock-Out Mice: Looking for Any Loss-of-Function Phenotype Related to Alzheimer’s Disease

• Main Authors: Alice Rossi, Luisa Galla, Chiara Gomiero, Lorena Zentilin, Mauro Giacca, Valentina Giorgio, Tito Calì, Tullio Pozzan, Elisa Greotti, Paola Pizzo
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: Cells
• Subjects: Alzheimer′s disease; presenilin 2; PS2–/–; Ca²⁺ signaling; mitochondria; bioenergetics
• Online Access: https://www.mdpi.com/2073-4409/10/2/204

Alzheimer′s disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial forms of AD (FAD) are caused by mutations in amyloid precursor protein (<i>APP</i>), presenilin 1 (<i>PSEN1</i>) and presenilin 2 (<i>PSEN2</i>) genes. Presenilin 1 (PS1) and its homologue, presenilin 2 (PS2), represent, alternatively, the catalytic core of the γ-secretase complex that, by cleaving APP, produces neurotoxic amyloid beta (Aβ) peptides responsible for one of the histopathological hallmarks in AD brains, the amyloid plaques. Recently, <i>PSEN1</i> FAD mutations have been associated with a loss-of-function phenotype. To investigate whether this finding can also be extended to <i>PSEN2</i> FAD mutations, we studied two processes known to be modulated by PS2 and altered by FAD mutations: Ca²⁺ signaling and mitochondrial function. By exploiting neurons derived from a <i>PSEN2</i> knock-out (PS2–/–) mouse model, we found that, upon IP₃-generating stimulation, cytosolic Ca²⁺ handling is not altered, compared to wild-type cells, while mitochondrial Ca²⁺ uptake is strongly compromised. Accordingly, PS2–/– neurons show a marked reduction in endoplasmic reticulum–mitochondria apposition and a slight alteration in mitochondrial respiration, whereas mitochondrial membrane potential, and organelle morphology and number appear unchanged. Thus, although some alterations in mitochondrial function appear to be shared between PS2–/– and FAD-PS2-expressing neurons, the mechanisms leading to these defects are quite distinct between the two models. Taken together, our data appear to be difficult to reconcile with the proposal that FAD-PS2 mutants are loss-of-function, whereas the concept that PS2 plays a key role in sustaining mitochondrial function is here confirmed.