Journal
ACTA NEUROPATHOLOGICA
Volume 124, Issue 2, Pages 199-208Publisher
SPRINGER
DOI: 10.1007/s00401-012-0980-x
Keywords
Abeta; Mitochondrial congenic mice; Conplastic; Alzheimer's disease; Amyloid-beta; Microglia; Mitochondria
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Funding
- county of Mecklenburg-Western Pomerania (LGF)
- Excellence Initiative [69027037/290100/2010-UR 09 020]
- INF Rostock
- NIH [RR-00165]
- CART Foundation
- German Science Foundation
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Several lines of evidence link mutations and deletions in mitochondrial DNA (mtDNA) and its maternal inheritance to neurodegenerative diseases in the elderly. Age-related mutations of mtDNA modulate the tricarboxylic cycle enzyme activity, mitochondrial oxidative phosphorylation capacity and oxidative stress response. To investigate the functional relevance of specific mtDNA polymorphisms of inbred mouse strains in the proteostasis regulation of the brain, we established novel mitochondrial congenic mouse lines of Alzheimer's disease (AD). We crossed females from inbred strains (FVB/N, AKR/J, NOD/LtJ) with C57BL/6 males for at least ten generations to gain specific mitochondrial conplastic strains with pure C57BL/6 nuclear backgrounds. We show that specific mtDNA polymorphisms originating from the inbred strains differentially influence mitochondrial energy metabolism, ATP production and ATP-driven microglial activity, resulting in alterations of cerebral beta-amyloid (A beta) accumulation. Our findings demonstrate that mtDNA-related increases in ATP levels and subsequently in microglial activity are directly linked to decreased A beta accumulation in vivo, implicating reduced mitochondrial function in microglia as a causative factor in the development of age-related cerebral proteopathies such as AD.
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