Mitochondrial permeability transition pore in Alzheimer's disease: cyclophilin D and amyloid beta

Abstract

Amyloid beta (Abeta) plays a critical role in the pathophysiology of Alzheimer's disease. Increasing evidence indicates mitochondria as an important target of Abeta toxicity; however, the effects of Abeta toxicity on mitochondria have not yet been fully elucidated. Recent biochemical studies in vivo and in vitro implicate mitochondrial permeability transition pore (mPTP) formation involvement in Abeta-mediated mitochondrial dysfunction. mPTP formation results in severe mitochondrial dysfunction such as reactive oxygen species (ROS) generation, mitochondrial membrane potential dissipation, intracellular calcium perturbation, decrease in mitochondrial respiration, release of pro-apoptotic factors and eventually cell death. Cyclophilin D (CypD) is one of the more well-known mPTP components and recent findings reveal that Abeta has significant impact on CypD-mediated mPTP formation. In this review, the role of Abeta in the formation of mPTP and the potential of mPTP inhibition as a therapeutic strategy in AD treatment are examined.

Figure 1

Cyclophilin D expression levels. Mitochondria were prepared from indicated brain regions of human AD/Non- AD (n = 9 – 12 per group) (Panel A) or from cortices of the indicated mice at different ages (n = 6 –10 per group) (Panel B). Isolated mitochondria were then subjected to SDS PAGE followed by the addition of anti cyclophilin D Ig G. The cyclophilin D expression level was normalized with cytochrome C oxidase. * P < 0.05. Figures are cited from [18].

Figure 2

Age dependent mitochondrial calcium retention capacity (CRC) change: (Panel A) Brain mitochondrial CRC was compared between nonTg and mAPP mice at 3, 6, 12 and 24 months of age (n = 4–6). Substantially decreased CRC of mAPP mitochondria in comparison to other genotypes was detected after the age of 6 months. * P < 0.05. (Panel B) CRC was compared between brain mitochondria from the indicated mice at the ages of 12 and 24 months respectively (n = 4– 6 for each group). mAPP mitochondria were treated with cyclosporine A (1 μM). *, #: P < 0.05 vs other genotypes of mice. Figures are cited and conflated from [18, 22].

Figure 2

Age dependent mitochondrial calcium retention capacity (CRC) change: (Panel A) Brain mitochondrial CRC was compared between nonTg and mAPP mice at 3, 6, 12 and 24 months of age (n = 4–6). Substantially decreased CRC of mAPP mitochondria in comparison to other genotypes was detected after the age of 6 months. * P < 0.05. (Panel B) CRC was compared between brain mitochondria from the indicated mice at the ages of 12 and 24 months respectively (n = 4– 6 for each group). mAPP mitochondria were treated with cyclosporine A (1 μM). *, #: P < 0.05 vs other genotypes of mice. Figures are cited and conflated from [18, 22].

Figure 3

Age dependent mitochondrial swelling change in response to Calcium. Brain mitochondria isolated from the indicated mice at 3, 6 12 and 24 months old (n = 4–10 for each group) were subjected to measured swelling induced by calcium (500 nmol/mg mitochondrial fraction). Decreased amplitude (percentage of initial OD at 540 nm) at the end of the test was compared among groups. 1 μM cyclosporine A was used in the treatment of mAPP mitochondria. * P < 0.05. Figures are cited and conflated from [18, 22].

Figure 4

Schematic figure: Aβ increases cyclophilin D expression level and interacts with cyclophilin D. Further, Aβ is involved in intracellular calcium and ROS perturbations and mitochondrial respiration dysfunction. By decreasing the threshold of mPTP due to these effects, Aβ facilitates the formation of mPTP resulting in mitochondrial perturbations including increased ROS generation, exacerbated perturbation of calcium metabolism, and mitochondrial membrane potential collapse. These severe mitochondrial perturbations lead to multiple cellular stresses, neuron death and finally deficits in learning/memory ability.