Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity

Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer's disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+ (mitoCa(2+)) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa(2+) overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.

Automated summary

The loss of central mitochondrial fission protein Drp1 worsens learning and memory in mice expressing mutant hAPP in neurons, leading to mitochondrial Ca2+ overload. This suggests a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.