PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia, affecting ~10% of the population over 65. Processing amyloid-beta precursor protein (APP) into amyloid-beta peptide (Aβ) is an important and fundamental aspect of AD pathogenesis. However, the signaling pathways that control this process are not well defined. Mitochondrial dysfunction is a prominent early feature in susceptible neurons in the brain of patients with AD and plays a critical role in AD pathogenesis. APP and its metabolic fragments are known to localize to mitochondria where they negatively influence mitochondrial function. Conversely, neurons with impaired mitochondrial function and bioenergetics also contribute to APP processing and synaptic loss. Although evidence suggests that APP-mitochondrial interactions are important for the cognitive deficits and amyloid genesis in AD, the field lacks a detailed understanding of the mechanisms that coordinate APP processing and functional mitochondrial deficiency. The coiled-coil-helix-coiled-coil-helix domain-containing protein 6 (CHCHD6) is an evolutionarily conserved nucleus-encoded mitochondrial protein. CHCHD6 is a core component of the mitochondrial contact site and cristae organization system (MICOS), which controls mitochondrial respiration and redox regulation, lipid homeostasis, and membrane ultrastructure and dynamics. Recent proteomics studies have shown a decrease in CHCHD6 in brain samples of AD patients and AD mice. However, the role of CHCHD6 in AD pathology is unknown. Our preliminary studies have revealed a previously unidentified role of CHCHD6 in the regulation of APP-mediated neuropathology and cognitive deficiency. The objective of this application is to determine the role of CHCHD6-mediated AD pathology at both mechanistic and therapeutic levels. In Aim 1, we will determine the causes and consequences of CHCHD6 loss of function in AD models. In Aim 2, we will dissect the mechanism of CHCHD6 loss in AD pathology. In Aim 3, we will determine whether compensation for the loss of CHCHD6 in AD mice alleviates neuropathology and cognitive deficits. If successful, these studies will establish CHCHD6 as a key molecule linking APP processing, lipid disturbance, and mitochondrial dysfunction and advance our understanding of AD pathology. The findings generated by this project will also have a significant impact on AD research by identifying CHCHD6 as a novel target for limiting mitochondrial dysfunction, amyloid pathology, and cognitive deficits in AD.