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 Ca (mitoCa) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca. This mitoCa overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.
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| http://dx.doi.org/10.1016/j.jbc.2021.100469 | DOI Listing |
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