Abstract
The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α 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 PGC1α have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer’s disease (AD) patients and animal models of amyloidosis, PGC1α expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1α resulted in reduced amyloid-β (Aβ) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of Aβ. These results provide evidence pointing toward PGC1α 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 PGC1α and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1α can be neuroprotective in AD and the pre-clinical treatments that have been explored so far.
Highlights
Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC1) is a group of transcriptional regulators for a variety of transcription factors and nuclear receptors, which consists of three subtypes, PGC1α, PGC1β, and the PGC-related coactivator (PRC) [1]
We focus on the role of PGC1α in Alzheimer’s disease (AD), the promising treatments based on its activation
PGC1α activation, either via drugs that increase its levels or the activation of transcription factors regulated by PGC1α, results in reductions in Alzheimer pathology and improvements in behaviour
Summary
Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC1) is a group of transcriptional regulators for a variety of transcription factors and nuclear receptors, which consists of three subtypes, PGC1α, PGC1β, and the PGC-related coactivator (PRC) [1]. Since the early 2000s, PGC1α has attracted interest because of its important role in metabolic processes (including gluconeogenesis, glucose transport, and fatty acid oxidation), mitochondrial biogenesis, peroxisomal remodelling, and detoxification of reactive oxygen species (ROS) [2] These effects are mediated through the regulation of a number of transcription factors, including nuclear respiratory factors (NFRs) NRF-1 and NRF-2 (interacting with Tfam, which drives transcription and replication of mtDNA), PPARs (PPARα, PPARδ/β, and PPARγ), thyroid hormone, glucocorticoid, oestrogen, and ERRs (oestrogen-related receptors) α and γ [3] (ERRα, ERRβ, and ERRγ), initiator element binding factor (YY1), myocyte-specific enhancer factors (MEF-2A, MEF-2C, MEF-2D), forkhead box O1 (FOXO1), and others [4]. Conditional knockout of PGC1α in the central nervous system (CNS) has revealed limited alterations in metabolic processes and its involvement in the regulation of a different category of genes linked with brain activity, including synaptotagmin 2, complexin 1, and interneuron genes [15,16,17,18]. We focus on the role of PGC1α in Alzheimer’s disease (AD), the promising treatments based on its activation
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