The Role of PGC1α in Alzheimer's Disease and Therapeutic Interventions

The peroxisome proliferator-activated receptor co-activator-1 alpha (PGC1 alpha) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1 alpha has been implicated in the control of mitochondrial biogenesis, the regulation of the synthesis of ROS and inflammatory cytokines, as well as genes controlling metabolic processes. The levels of PGC1 alpha have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer's disease (AD) patients and animal models of amyloidosis, PGC1 alpha expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1 alpha resulted in reduced amyloid-beta (A beta) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of A beta. These results provide evidence pointing toward PGC1 alpha activation as a new therapeutic avenue for AD, which has been supported by the promising observations of treatments with drugs that enhance the expression of PGC1 alpha and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1 alpha can be neuroprotective in AD and the pre-clinical treatments that have been explored so far.