Amyloid-β-related mitochondrial impairment. Mitochondria were found to be the target for amyloid-β (Aβ), which interacts with several proteins, leading to mitochondrial dysfunction. Indeed, Aβ was found in the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM) as well as in the matrix. The interaction of Aβ with the OMM affects the transport of nuclear-encoded mitochondrial proteins, such as subunits of the electron transport chain complex IV, into the organelle via the translocase of the outer membrane (TOM) import machinery. Moreover, Aβ disturbs the activity of several enzymes, such as pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (αKGDH), decreasing NADH reduction, and the electron transport chain enzyme complex IV, reducing the amount of hydrogen that is translocated from the matrix to the intermembrane space (IMS), thus impairing the mitochondrial membrane potential (MMP). Taken together, these events cause abnormal mitochondrial electron activities, leading to decreased complex V activity and so to a drop in ATP levels, in addition to increasing reactive oxygen species (ROS) generation. Moreover, ROS induce peroxidation of several mitochondrial macromolecules, such as mitochondrial DNA (mtDNA) and mitochondrial lipids, contributing to mitochondrial impairment in the mitochondrial matrix. The complex of Aβ bound to binding alcohol dehydrogenase (ABAD) impairs the binding of NAD+ to ABAD, changes mitochondrial membrane permeability and reduces activities of respiratory enzymes, inducing further ROS production and leading to mitochondrial failure. Aβ binding also activates Fis1 (fission protein) and promotes increased mitochondrial fragmentation; this increased mitochondrial fragmentation produces defective mitochondria that ultimately damage neurons. Furthermore, Aβ binding to cyclophilin D (CypD) enhances the protein translocation to the inner membrane, favouring the opening of the mitochondrial permeability transition pore, formed by the adenine nucleotide translocator (ANT) and voltage-dependent anion channels (VDACs). Cyt C, cytochrome C; DLP1, dynamin-like protein 1; PDH, pyruvate dehydrogenase; ProAp, proapoptotic factors; SOD, superoxide dismutase; TCA, tricarboxylic acid; TIM, translocase of the inner membrane.