Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss of neurons in the brain. Under the microscope, neuronal accumulation of abnormal tau proteins and amyloid plaques are two pathological hallmarks in affected brain regions. Although the detailed mechanism of the pathogenesis of AD is still elusive, a large body of evidence suggests that damaged mitochondria likely play fundamental roles in the pathogenesis of AD. It is believed that a healthy pool of mitochondria not only supports neuronal activity by providing enough energy supply and other related mitochondrial functions to neurons, but also guards neurons by minimizing mitochondrial related oxidative damage. In this regard, exploration of the multitude of mitochondrial mechanisms altered in the pathogenesis of AD constitutes novel promising therapeutic targets for the disease. In this review, we will summarize recent progress that underscores the essential role of mitochondria dysfunction in the pathogenesis of AD and discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.

Mitochondrial dysfunction is a prominent feature of Alzheimer9s disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-β-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.

Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid β on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that ≈40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with β-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or Aβ-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid β production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.

J. Neurochem. (2012) 120, 419–429. Mitochondrial dysfunction is a prominent feature of Alzheimer’s disease (AD) brain. Our prior studies demonstrated reduced mitochondrial number in susceptible hippocampal neurons in the brain from AD patients and in M17 cells over‐expressing familial AD‐causing amyloid precursor protein (APP) mutant (APPswe). In the current study, we investigated whether alterations in mitochondrial biogenesis contribute to mitochondrial abnormalities in AD. Mitochondrial biogenesis is regulated by the peroxisome proliferator activator receptor gamma‐coactivator 1α (PGC‐1α)‐nuclear respiratory factor (NRF)‐mitochondrial transcription factor A pathway. Expression levels of PGC‐1α, NRF 1, NRF 2, and mitochondrial transcription factor A were significantly decreased in both AD hippocampal tissues and APPswe M17 cells, suggesting a reduced mitochondrial biogenesis. Indeed, APPswe M17 cells demonstrated decreased mitochondrial DNA/nuclear DNA ratio, correlated with reduced ATP content, and decreased cytochrome C oxidase activity. Importantly, over‐expression of PGC‐1α could completely rescue while knockdown of PGC‐1α could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in APPswe M17 cells, suggesting reduced mitochondrial biogenesis is likely involved in APPswe‐induced mitochondrial deficits. We further demonstrated that reduced expression of p‐CREB and PGC‐1α in APPswe M17 cells could be rescued by cAMP in a dose‐dependent manner, which could be inhibited by PKA inhibitor H89, suggesting that the PKA/CREB pathway plays a critical role in the regulation of PGC‐1α expression in APPswe M17 cells. Overall, this study demonstrated that impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD.