Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease

By Heng Du, Lan Guo, F. Fang, Doris Chen, A. Sosunov, G. McKhann, Yilin Yan, Chunyu Wang, Hong Zhang, J. Molkentin and 5 more. Nature Medicine, 2008

914 citations recorded by the source corpus.

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-β protein (Aβ) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Aβ- and Ca2+-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 Aβ- 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 Aβ-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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/f65371132bb777011b9e21d3726b10f1bd708445

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. M. Calkins
2. Angelina V. Vaseva
3. M. Mańczak
4. P. Reddy
5. Plamena R. Angelova
6. A. Abramov
7. E. K. Kim
8. E. Choi

In Physiology

1. M. Calkins
2. M. Mańczak
3. P. Reddy
4. A. Abramov
5. E. K. Kim
6. E. Choi
7. P. Mao
8. C. Zhong

Citations in the corpus

• Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. (2011, background): “Recently, Yan and colleagues reported the interaction of Ab with the mitochondrial matrix proteins CypD and ABAD (42,43).”
• Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. (2011, methodology): “At 16 DIV, we found that a portion of A11 immunopositive oligomeric Ab colocalized with mitochondria, confirming previous reports (21,27,28,34).”
• Compromised MAPK signaling in human diseases: an update (2015, background): “Furthermore, CypD deficiency protects against Aβ-induced neuronal death (Du et al. 2008) (Fig.”
• p53 opens the mitochondrial permeability transition pore to trigger necrosis (2012, background): “Inhibiting PTP or ablating CypD in AD mice renders their cortical brain mitochondria resistant to PTP opening and improves their cognitive functions (Du et al., 2008).”
• Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, neutral): “Moreover, Ab can interact with Cyclophilin-D, the mitochondrial modulatory component of mitochondrial mPTP, and increase synaptic stress with disturbing effects on learning and memory of AD patients (Du et al., 2008).”
• Neuronal Cell Death. (2018, neutral): “There are studies suggesting that mPT may be involved in pathogenesis of Alzheimer’s disease as the absence of cyclophilin D protects against beta amyloid-induced mitochondrial dysfunction and neuronal death, and also improves learning and memory functions in mouse models of Alzheimer’s disease (183”
• TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “These observations potentially suggest destabilization and, thus, opening of the mitochondrial permeability transition pore (mPTP) (Du et al., 2008; Nguyen et al., 2011), which can lead to mtDNA release (Garcı́a and Chávez, 2007).”
• Role of mitochondrial ROS in the brain: from physiology to neurodegeneration (2018, background): “[47] Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, GunnMoore FJ, Vonsattel JP, Arancio O, Chen JX, & Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.”
• Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. (2013, background): “The definitive evidence has shown that Ab accumulation in mitochondria of AD patients and mouse models occurs before extracellular amyloid deposition and increases with age (Devi et al., 2006; Du et al., 2008; Hirai et al., 2001; Manczak et al., 2006).”
• Synaptic energy use and supply. (2012, neutral): “Mitochondrial damage by Ab results in oxidative stress, opening of the mitochondrial permeability transition pore and thus apoptosis (Sheehan et al., 1997; Du et al., 2008).”
• Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model (2010, methodology): “CypD is elevated during the aging of both human and mouse brains (26, 27).”
• A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis (2011, background): “, and they suggest that neuroprotective strategies that target mitochondrial pathology might be effective not only in classical neurodegenerative disease but also in multiple sclerosi”
• Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease (2017, background): “CypD knock-out reduced oxidative stress and apoptosis, and cypD knock-out preserved cognitive performance in A PP transgenic mice [36].”