*4.2. Alzheimer's Disease*

Alzheimer's disease (AD) is the most commonly occurring form of neurodegeneration, and growing evidence is linking it to mitochondrial dysfunction at all levels of AD neuropathology. AD is characterised by the death or loss of neurons in specific, susceptible areas of the brain, as well as by the presence of two pathological hallmarks: extracellular senile plaques and neurofibrillary tangles (NFTs) [287].

Senile plaques are deposits of accumulated amyloid-beta peptide (Aβ), a 40–42 amino acid peptide that is produced by specific, sequential proteolytic cleavages of amyloid precursor protein (APP). The biology of APP processing and its relevance in AD is reviewed in great detail in a previous review [287]. In a study carried out in mitochondria from human AD brains, APP has been found to accumulate in the TOM40 channel, forming a stable complex of ~480 kDa (Table 2) [260]. It also accumulates with both TOM40 and TIM23 to form a supercomplex of ~620 kDa [260]. Interestingly, mitochondrial APP levels varied both among patients, corresponding to the severity of AD, as well as across brain regions, with higher levels displayed in the regions of the brain that are more vulnerable to AD: the cortex, hippocampus, and amygdala [260]. Furthermore, the levels of APP accumulation in the mitochondria of AD brains directly correlates with mitochondrial dysfunction [260], suggesting that APP-mitochondrial translocase complex formation and aggregation may in fact be a causative factor in AD progression.

Furthermore, a study in PC12 cells showed that chronic, sub-lethal Aβ exposure induces a significant reduction in mitochondrial protein import, and that this, when sustained over long periods, leads to mitochondrial dysfunction highlighted by a reduction in ∆ψ, altered mitochondrial morphology, and increased ROS production (Table 2) [261]. This consequential negative impact on mitochondrial function is likely due to the loss of important proteins that are usually imported via TOM40, such as proteins necessary for respiratory complex activity and assembly, as well as ROS scavenging proteins.

The second characteristic hallmark of AD, neurofibrillary tangles, insoluble aggregations made up primarily of hyperphosphorylated Tau protein, is a symptom of not only AD, but of all tauopathies. Cell line studies have shown that various forms of aggregationprone Tau (wildtype, hyperphosphorylated, or caspase cleaved N-terminal fragment) are imported into mitochondria and localised to the IMS and OMM (Table 2) [262,263]. Whilst, to the best of our knowledge, no studies have specifically looked at the impact of Tau on mitochondrial protein import efficiency, the body of evidence highlighting Tau accumulation in mitochondria suggests this would be worth investigating.
