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Cyclophilin D Deficiency Attenuates Mitochondrial and Neuronal ARTICLES Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease Heng Du1, Lan Guo1, Fang Fang1, Doris Chen1, Alexander A Sosunov2, Guy M McKhann2, Yilin Yan3, Chunyu Wang3, Hong Zhang4,5, Jeffery D Molkentin6, Frank J Gunn-Moore7, Jean Paul Vonsattel4, Ottavio Arancio4,5, John Xi Chen8 & Shi Du Yan1,4,5 Cyclophilin D (CypD, encoded by Ppif ) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-b protein (Ab) potentiates mitochondrial, neuronal http://www.nature.com/naturemedicine and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Ab-andCa2+-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Ab- and oxidative stress–induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer’s disease mouse model and alleviates Ab-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer’s disease. Blockade of CypD may be a therapeutic strategy in Alzheimer’s disease. Mitochondrial dysfunction is a feature of the Alzheimer’s disease apoptogenicpotentialfromtheinnermembranespace19–21.The brain1–5. Recent studies have highlighted the role of mitochondrial mPTP is thought to involve the voltage-dependent anion channel Nature Publishing Group Group Nature Publishing 8 Ab in Alzheimer’s disease pathogenesis6–15.Ab species have been in the outer membrane, the adenine nucleotide translocase in the 20,22–25 200 found in the mitochondria of both Alzheimer’s disease brain and inner membrane and CypD in the mitochondrial matrix . © transgenic mouse models of Alzheimer’s disease overexpressing CypD, a peptidylprolyl isomerase F, resides in the mitochondrial Ab6,7,9,13–16. Accumulation of Ab in mitochondria occurs before matrix and associates with the inner mitochondrial membrane extracellular amyloid deposition and increases with age. Accord- during the opening of the mPTP. Oxidative and other cellular ingly, Ab is linked to the mitochondrial malfunction observed in stresses promote CypD translocation to the inner membrane26–31, theAlzheimer’sdiseasebrainandmousemodelsofAlzheimer’s and this translocation acts as a key factor to trigger the opening of disease6,7,17. For instance, increased expression of amyloid-binding the mPTP. Moreover, recent studies show that a genetic deficiency alcohol dehydrogenase, an intracellular Ab-binding protein, in CypD protects from Ca2+- and oxidative stress–induced cell exacerbates Ab-mediated mitochondrial and neuronal stress8,9. death and that CypD functions as a necessary component of the Ab can also directly disrupt mitochondrial function, and such mPTP30,32–34.TheobservationsthatAb progressively accumulates disruption causes oxidative stress4,18. However, the essential intra- in brain mitochondria from individuals with Alzheimer’s disease cellular mechanisms underlying Ab-mediated mitochondrial and Alzheimer’s disease model mice and that oxidative stress is malfunction have yet to be elucidated. enhanced in an Ab-rich environment led us to explore the The mitochondrial permeability transition pore (mPTP) has a mechanisms underlying Ab-mediated mitochondrial dysfunction. central role in both necrotic and apoptotic neuronal cell death. Our present study offers new insights into the mechanism under- Opening of the mPTP collapses the membrane potential and lying CypD-dependent mPTP opening and synaptic function amplifies apoptotic mechanisms by releasing proteins with during the pathogenesis of Alzheimer’s disease. 1Departments of Surgery and 2Neurosurgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA. 3Biology Department, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180-3590, USA. 4Department of Pathology and 5Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA. 6Department of Pediatrics, University of Cincinnati, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. 7School of Biology, 79 North Street, University of St. Andrews, St. Andrews KY16 9TS, Scotland. 8Department of Neurology, Memorial Sloan-Kettering Cancer Center, Cornell University, 1275 York Avenue, New York, New York 10065, USA. Correspondence should be addressed to S.D.Y. ([email protected]). Received 4 January; accepted 25 August; published online 21 September 2008; doi:10.1038/nm.1868 NATURE MEDICINE VOLUME 14 [ NUMBER 10 [ OCTOBER 2008 1097 ARTICLES a 30 b c 90 80 25 70 Aβ42 20 60 42 β 15 40 50 10 Aβ40 20 40 or A 30 5 β A 40 (resonance units) 42 (resonance units) 0 (resonance units) β 0 β A 10 A –5 –20 Aβ40–1 –150 –100 –50 0 50 100 150 –150 –100 –50 0 50 100 150 –50 050100 150 200 250 300 Time (s) Time (s) Time (s) 120 d e 300 f 250 100 250 200 Aβ42 80 200 60 150 150 42 oligomers 40 β 100 100 β 40 oligomers A 40 β 42 oligomers β A 20 50 (resonance units) A (resonance units) (resonance units) 50 40 or A 0 0 β A –20 –50 Aβ40–1 –100 –50 0 50 100 150 –100 –50 0 50 100 150 200 –50 0 50 100 150 200 Time (s) Time (s) Time (s) ghij1 2 3 4 5 6 7 8 kDa 14 Aβ40 * 1 2345kDa 70 * 30.5 β 60 12 A 42 * 14.5 21.5 50 10 6.5 http://www.nature.com/naturemedicine β 40 14.5 8 A 3.5 30 Aβ42 6.5 6 20 (AD/ND) COX IV Aβ40 3.5 Intensity units 4 Fold increase Fold 10 2 0 COX IV –/– –/– f –/– 0 f ND AD mAPP- Ppi NonTg mAPP mAPP –/– f ND AD Ppi mAPP- Ppi NonTg mAPP Ppif Figure 1 Interaction of CypD with Ab.(a–f) Surface plasmon resonance (SPR) analysis of CypD-Ab interaction. Globally fit data (black lines) were overlaid with experimental data (red lines). (a,b) Sensorgram of Ab40 (a)orAb42 (b) interaction with CypD immobilized on the CM5 chip. (c) CypD interaction with different types of Ab.Ab42 (20 mM), Ab40 (60 mM) and sequence-reversed Ab40 (60 mM) bind to CypD immobilized on the CM5 chip. (d,e) Sensorgram of CypD interaction with oligomers of Ab40 (d)orAb42 (e) immobilized on the CM5 chip. (f) CypD interaction with different types of oligomeric and reversed Ab immobilized on the CM5 chip. (g–j) Coimmunoprecipitation of CypD and Ab in brain mitochondria from human subjects with Alzheimer’s disease and Nature Publishing Group Group Nature Publishing 8 transgenic mice. Representative immunoblots show the presence of CypD-Ab complex in temporal cortical mitochondria of subjects with Alzheimer’s disease (AD) or subjects without Alzheimer’s disease (ND) (g) and in the cortical mitochondria of transgenic mice at 12 months of age (i). Lower panels of g 200 and i indicate immunoblotting of the same preparations of mitochondria with antibody to COX IV, showing equal amount of mitochondrial protein used © in the experiment. Lane 4 in panel g is an immunoblot for Ab40 peptide (5 ng). (h,j) Densitometry of all immunoreactive bands generated from coimmunoprecipitation results (AD, n ¼ 9; ND, n ¼ 6; transgenic mice, n ¼ 4–6 per group). *P o 0.0001 compared to ND or other groups of mice. NonTg, nontransgenic. RESULTS cortical mitochondria of Alzheimer’s disease brains (Fig. 1g) but not Interaction of CypD with mitochondrial Ab (or very little) in those of non–Alzheimer’s disease control brains In view of the increased expression of CypD associated with amyloid (Fig. 1g). Ab-immunoreactive bands disappeared when the antibody pathology in addition to aging (Supplementary Fig. 1a–i online), we to CypD was replaced by preimmune IgG (Fig. 1g). Densitometry explored whether CypD serves as a mitochondrial target potentiating of all immunoreactive bands combined revealed that CypD-Ab Ab-induced cellular perturbation. We first examined the interaction of complexes were increased by 10–13-fold in Alzheimer’s disease cortical CypD with Ab by surface plasmon resonance (SPR)35,36. Recombinant mitochondria compared to non–Alzheimer’s disease cortical mito- human CypD protein (Supplementary Fig. 2a online) bound Ab in a chondria (Fig. 1h). In parallel, mitochondrial Ab was increased by dose-dependent manner (Fig. 1a–f). The CypD-Ab interaction was nine- to tenfold in Alzheimer’s disease brain (Supplementary specific, because reversed-sequence Ab peptide showed no binding Fig. 2b), indicating an association between CypD-Ab complex and with CypD (Fig. 1c,f), and antibodies against either Ab or CypD thepresenceofmitochondrialAb. Furthermore, CypD-Ab complex inhibited binding (data not shown). The equilibrium dissociation was also found in the cortical mitochondria of transgenic mAPP mice constants (Kd)forAb40 (Ab peptide residues 1–40), Ab42 (Ab overexpressing a mutant form of human amyloid precursor protein peptide residues 1–42), oligomeric Ab40 and oligomeric Ab42 were (APP) and Ab, but not in mitochondria from CypD-deficient mAPP 1.7 mM, 164 nM, 227 nM and 4 nM, respectively. Therefore, Ab mice (mAPP-Ppif –/–), CypD-null (Ppif –/–)ornontransgenicmice oligomers and Ab42 have higher affinity for binding to CypD. (Fig. 1i–j). Transgenic CypD-null mice are described in Supplemen- To determine whether CypD and Ab actually interact in patho- tary Figure 2c–g. These results indicate that the CypD-Ab interaction physiologically relevant settings, we subjected mitochondrial proteins occurs in Alzheimer’s disease brain and transgenic mice with to immunoprecipitation with an antibody to CypD followed by Alzheimer’s-like pathology. immunoblotting with an antibody to Ab. CypD-Ab complexes, Confocal and electron microscopic studies confirmed colocalization corresponding to Ab-immunoreactive bands, were detected in the of CypD and Ab in mitochondria (Fig.
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