Compelling evidence suggest that mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease and plays a critical role in the pathogenesis of AD, yet the underlying molecular mechanism remains incompletely understood. Studies from my group and several other groups demonstrated reduced PGC-1? expression and impaired mitochondrial biogenesis signaling in hippocampus from AD patients and in APP transgenic mouse models. We demonstrated that APPswe mutant causes reduced PGC-1? and impaired mitochondrial biogenesis in neurons likely through the PKA/CREB pathway. Our preliminary studies demonstrated that PGC-1? overexpression restores the mitochondrial biogenesis signaling, alleviates mitochondrial deficits such as abnormal mitochondrial dynamics/distribution and leads to improved mitochondrial function in neuronal cells. These studies suggest that impaired mitochondrial biogenesis signaling plays a critical role in mitochondrial dysfunction which adversely affected neuronal function and contributed to the pathogenesis of AD. It remains to be determined whether and how impaired mitochondrial biogenesis is causally involved in mitochondrial/neuronal dysfunction and cognitive deficits in animal models of AD in vivo. Based on studies in other neurodegenerative diseases and our preliminary studies, we developed the working hypothesis that PGC-1? overexpression to restore mitochondrial biogenesis plays a neuroprotective role in animal models of AD. A recent study reported a negative impact of PGC- 1? overexpression on mitochondrial function and AD-related deficits in one APP Tg mouse model. However, due to the important concerns such as a lack of mitochondrial biogenesis activation on this negative study, the critical role of PGC-1? and mitochondrial biogenesis in the pathogenesis of AD in vivo remains unanswered. Given the critical role of PGC-1? and mitochondrial biogenesis in mitochondrial/neuronal function, in our opinion, it actually makes a stronger case for a more rigorous characterization of the effects of PGC-1? in AD mouse models to resolve the controversy which will likely pave the way for developing treatment targeting mitochondrial biogenesis in AD. Based on the literature and our preliminary study, we also propose to explore the mechanism underlying the effects of PGC-1? on mitochondrial dynamics and axonal transport which will reveal novel regulatory mechanisms between mitochondrial biogenesis and dynamics/transport and suggest the central role of PGC-1? in rescuing mitochondrial deficits broader than biogenesis in AD.
Impaired mitochondrial biogenesis is demonstrated in AD patients and APP transgenic animal models and in vitro studies suggested a critical role of impaired mitochondrial biogenesis in mediating A?- or APP mutant-induced mitochondrial dysfunction and neuronal dysfunction. In this application, we proposed to investigate the causal involvement of impaired mitochondrial signaling in the pathogenesis of AD in vivo and explore the underlying mechanism which will likely pave the way for developing treatment targeting mitochondrial biogenesis in AD.
