Amyloid-beta-induced mitochondrial dysfunction

Amyloid-beta-induced mitochondrial dysfunction is a pathological process central to the progression of Alzheimer’s disease and other neurodegenerative disorders [1, 6]. It occurs when amyloid-beta (Aβ) peptides accumulate within neurons and localize to the mitochondria, where they interact with various proteins and membranes [3, 15]. This interaction leads to the inhibition of the electron transport chain (particularly Complexes III and IV), increased production of reactive oxygen species (ROS), and impaired calcium buffering [6, 17]. Furthermore, Aβ binds to the mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD), exacerbating oxidative stress and neuronal apoptosis [4, 9]. Therapeutic efforts to address this dysfunction include the use of mitochondria-targeted antioxidants like MitoQ, bioenergetic enhancers like elamipretide or NAD+ precursors, and small molecules that block the Aβ-ABAD interaction [7, 11, 14]. Despite its clear role in disease pathology, targeting this process remains difficult due to the complexity of mitochondrial signaling and the need for early clinical intervention [7, 8].

Other names

Aβ-induced mitochondrial dysfunctionMitochondrial cascade hypothesis in Alzheimer's diseaseAmyloid-beta-mediated mitochondrial toxicityIntramitochondrial amyloid-beta accumulation

Drugs targeting this process aim to mitigate mitochondrial damage by preventing the interaction between Amyloid-beta and mitochondrial proteins (e.g., ABAD), reducing oxidative stress via targeted antioxidants, stabilizing the mitochondrial membrane potential, and enhancing energy metabolism through the restoration of NAD+ levels [4, 7, 11, 14].