Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model - PubMed (original) (raw)

Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model

Heng Du et al. Neurobiol Aging. 2011 Mar.

Abstract

Mitochondrial stress is one of the early features of Alzheimer disease (AD). Mitochondrial Aβ has been linked to mitochondrial toxicity. Our recent study demonstrated that cyclophilin D (CypD) mediated mitochondrial permeability transition pore (mPTP) is an important mechanism for neuronal and synaptic stress induced by both Aβ and oxidative stress. In transgenic AD-type mice overexpressing mutant amyloid precursor protein (APP) and Aβ (mAPP), CypD deficiency improves mitochondrial and synaptic function and learning/memory up to 12 months old. Here we provide evidence of the protective effects of CypD deficiency in aged AD mice (22-24 months). Cyp D deficient mAPP mice demonstrate less calcium-induced mitochondrial swelling, increased mitochondrial calcium uptake capacity, preserved mitochondrial respiratory function and improved spatial learning/memory even in old age (known to be the age for late stage AD pathology and synaptic dysfunction). These data demonstrate that abrogation of CypD results in persistent life-long protection against Aβ toxicity in an Alzheimer's disease mouse model, thereby suggesting that blockade of CypD may be of benefit for Alzheimer disease treatment.

Copyright © 2009 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Disclosure statement: We have no conflicts of interest to disclose. We have no contract relating this research with any organization that could benefit financially from our research.

Figures

Fig. 1

Fig. 1

CypD expression in aged transgenic mice. Panel (A) densitometry of immunoreactive bands using NIH imageJ program (n = 8 mice per group; P < 0.001). Panels (B and C). Representative images of Western blots for CypD. Western blot for cytochrome c oxidase was used as a protein loading control showing an equal amount of protein added to each lane.

Fig. 2

Fig. 2

Cerebral Aβ levels in transgenic mice at age of 22–24 months. Panel (A) densitometry of Aβ immunoreactive bands by using NIH imageJ program. Panel (B) Representative images of Western blot for Aβ and β-actin. β-Actin was used as a protein loading control (n = 4–5 per group).

Fig. 3

Fig. 3

Effect of CypD deficiency on mitochondrial swelling and calcium uptake capacity. (A) Comparison of mitochondrial swelling among Tg mice cortical mitochondria (n = 4–5 mice per group; *P < 0.05 vs. nonTg mitochondria; #P < 0.001 vs. mAPP or nonTg mitochondria panel A1). Mitochondrial swelling was induced by the addition of 500 nmol calcium per mg mitochondrial protein. The addition of CSA completely rescued mAPP mitochondria from calcium-induced swelling (*P < 0.001 vs. mAPP/Ppif−/− mitochondria or mAPP mitochondria incubated with CSA panel A2). The calcium buffering capacity of mAPP mitochondria is much lower than that of nonTg, mAPP/Ppif−/− mitochondria or mAPP mitochondria with CSA (*P < 0.01; n = 4–6 mice per group panel B).

Fig. 4

Fig. 4

CypD translocation. Mitochondrial membrane and matrix were isolated from cortices of the indicated Tg mice and then subjected to Western blotting for CypD (n = 4 mice per group). Panel (A) indicates densitometry of CypD immunoreactive bands and panel (B) shows representative images of Western blotting for CypD and cytochrome c oxidase. Cytochrome c oxidase was used as a protein loading control indicating an equal amount of mitochondrial protein employed for each of the experiments.

Fig. 5

Fig. 5

Effect of CypD deficiency on mitochondrial respiratory function and cytochrome c oxidase activity in mAPP mice. Respiration control rate (RCR) in the cortical mitochondria from the indicated Tg mice at 22–24 months old (panel (A1)). RCR values are shown in panel (A2) (n = 4–5 mice per group, *P < 0.005 vs. nonTg, mAPP/Ppif−/− or Ppif−/− mitochondria and #P < 0.01 vs. nonTg or Ppif−/− mitochondria). Cytochrome c oxidase activity in the indicated Tg mice at 22–24 months old (panel (B1)). Value for cytochrome c oxidase activity (panel (B2)) (n = 4–5 mice per group, *P < 0.05 vs. other groups of mice).

Fig. 6

Fig. 6

Effect of CypD deficiency on spatial learning and memory. Mice were tested in a 6-arm radialwater maze.mAPPmice made more errors in locating the hidden platform than other groups of mice (*P < 0.01). mAPP/Ppif−/− mice demonstrated better performance than mAPP mice but worse than nonTg and Ppif−/− mice (#P < 0.01; n = 6–7 mice per group).

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