Figure 4.

Mitochondrial dysfunction in AD. Degenerating neurons in brain areas affected by Alzheimer disease (AD) (e.g. hippocampus and cerebral cortex) present typical intracellular neurofibrillary tangles (NFTs) and extracellular accumulation of β-amyloid plaques. Aβ is produced from the metabolism of amyloid precursor protein (APP) through sequential cleavage by β- and γ-secretases, and it is prone to form toxic oligomeric structures both inside and outside the cell. APP and Aβ can affect mitochondrial function by different mechanisms. APP is targeted to mitochondria, where it forms complexes with the translocases of the outer and inner membranes (TOM and TIM), which drive the import of mitochondrial proteins in cooperation with molecular chaperones. However, the presence of an acidic domain within APP might be responsible for preventing its translocation into mitochondria. As a consequence, the import of mitochondrial proteins, such as respiratory chain subunits, is reduced, and this event is associated with increased free radical generation and reduced activity of the electron-transport chain. Other aspects of amyloid metabolism involve mitochondria: intramitochondrial Aβ has been shown to interact with amyloid-β-binding alcohol dehydrogenase (ABAD) and to produce reactive oxygen species (ROS). Aβ also interacts with cytochrome c oxidase, thus decreasing the activity of complex IV (cIV). Furthermore, presequence peptidase PreP and HTRA2/OMI serine protease have been shown to degrade Aβ oligomers, thus providing a mechanism to detoxify this metabolite. Intramitochondrial Aβ directly interacts with cyclophilin D (CypD), a component of the mitochondrial permeability transition pore (mPTP), which is located in the mitochondrial matrix. This interaction makes the channel more sensitive to Ca²⁺ and stimulates mPTP opening, thus raising the permeability of the mitochondrial inner membrane (IM) and eventually disrupting the mitochondrial outer membrane (OM). As a result, deregulation of the mPTP opening determines a functional disorder that triggers cell death. Abbreviations: AD, Alzheimer disease; ATP, adenosine-5′-triphosphate; cI, complex I; cII, complex II; cIII, complex III; cV, complex V; HTRA2, HtrA2 serine peptidase; Δψ_m, mitochondrial membrane potential.