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Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model
Heng Du1, Lan Guo, Wensheng Zhang
1Department of Surgery, and Taub Institute for Research on Alzheimer's Disease and Aging Brain, College of Physicians & Surgeons of Columbia University, 650 West 168th Street, New York, NY 10032, USA.
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.
Insights
Blocking cyclophilin D (CypD) protects against Alzheimer disease (AD) pathology. CypD deficiency in aged AD mice preserved mitochondrial function and improved memory, suggesting CypD blockade as a potential AD treatment.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Alzheimer's Disease Research
Background:
- Mitochondrial stress and amyloid-beta (Aβ) toxicity are early features of Alzheimer disease (AD).
- Cyclophilin D (CypD) mediated mitochondrial permeability transition pore (mPTP) is implicated in neuronal and synaptic stress caused by Aβ and oxidative stress.
Purpose of the Study:
- To investigate the long-term protective effects of CypD deficiency in aged Alzheimer disease (AD) mouse models.
- To evaluate the impact of CypD abrogation on mitochondrial function and cognitive performance in late-stage AD.
Main Methods:
- Utilized transgenic AD-type mice (mAPP) with and without CypD deficiency.
- Assessed mitochondrial function (calcium-induced swelling, calcium uptake, respiratory function) in aged mice (22-24 months).
- Evaluated spatial learning and memory performance in aged mAPP mice with and without CypD deficiency.
Main Results:
- CypD deficient mAPP mice showed reduced calcium-induced mitochondrial swelling and enhanced mitochondrial calcium uptake capacity.
- Preserved mitochondrial respiratory function was observed in aged CypD deficient mAPP mice.
- Improved spatial learning and memory were evident in aged CypD deficient mAPP mice, despite advanced AD pathology.
Conclusions:
- CypD deficiency confers persistent, life-long protection against Aβ toxicity in an AD mouse model.
- Abrogation of CypD preserves mitochondrial and synaptic function and cognitive abilities even in old age.
- Targeting CypD represents a promising therapeutic strategy for Alzheimer disease treatment.
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