| Summary: | 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: Ca<sup>2+</sup> signaling and mitochondrial function. By exploiting neurons derived from a <i>PSEN2</i> knock-out (PS2–/–) mouse model, we found that, upon IP<sub>3</sub>-generating stimulation, cytosolic Ca<sup>2+</sup> handling is not altered, compared to wild-type cells, while mitochondrial Ca<sup>2+</sup> 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.
|
|---|
