In this project we will develop preclinical data to support use of a novel biological mitochondrial gene therapy (rhTFAM) to increase energy production in brains of mice with experimental Alzheimer's disease (AD). Impaired mitochondrial function has been described in both animal AD models and humans with early AD. We have found molecular genetic evidence for the loss of mitochondrial genes and signaling pathway control of mitochondrial mass (mitobiogenesis) in postmortem AD brains. In this proposal we will determine the extent of impairment of these mitochondrial functions in experimental AD mice. We will then treat the mice with rhTFAM, an novell human mitochondrial protein that we have shown can increase mitochondrial function in cell and animal models of diseases. rhTFAM also restores the memory function of aged mice while increasing mitochondrial function in their brains, suggesting that it has great potential to do the same for impaired cognition in AD patients. rhTFAM has been favorably reviewed by the FDA. The current proposal will provide critical data to support the use of rhTFAM in humans with AD.