AMP-Activated Protein Kinase (AMPK) signaling regulates the age-related decline of hippocampal neurogenesis




Wang, Brian S.


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Aging is the progressive decline of physiological function and increased vulnerability to disease and death. By the year 2050, 2 billion people will be over the age of 60. Accompanying this, the incidence of age-associated neurological diseases is expected to rise. Thus, there is an urgent need to find therapies to promote healthy brain aging. The finding that neurogenesis continues into adulthood allows us to target endogenous neurogenesis as a potential therapeutic. However, the number of stem cells can decrease by about 80% in the aged brain and is a main cause for the decrease in brain function. The reasons for the age-related decline in neurogenesis can be due to intrinsic factors such as cell metabolism, which have been studied but its role in neurogenesis remains largely unexplored. Interestingly, neural stem cells (NSCs) possess metabolically different characteristics from their differentiated progeny, suggesting the need for a shift in cellular metabolism to accommodate the requirements for neurogenesis. In the process of the metabolic shift, the AMP-activated protein kinase (AMPK) plays a pivotal role for controlling stem cell proliferation and differentiation as a cell's master metabolic regulator. Additionally, AMPK has been reported to control the functions of signaling pathways that regulate the aging process, which suggests its potential involvement in the age-related decline of neurogenesis. Therefore, we hypothesize that inhibition of AMPK signaling activation (phosphorylation) in the old brain will cause a concomitant increase in hippocampal neurogenesis. Our specific aim is to establish whether AMPK signaling plays a critical role in the age-related decline of hippocampal neurogenesis. Our objectives for this aim are to (i) determine the expression pattern of AMPK in the subgranular and subventricular zones of young-adult and old mice using immunohistochemistry and Western blotting; and (ii) examine the impact of loss or gain of AMPK activation on hippocampal neurogenesis in young-adult and old mice using pharmacological agents Compound C (AMPK inhibitor) and 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, AMPK activator). Our results show that (i) AMPK subunit isoforms are differentially expressed in the neurogenic regions – most are localized to the cytoplasm in the subgranular zone (SGZ) with the exception of α2 and β1, while most isoforms are found in the nucleus in the subventricular zone (SVZ) except α1; (ii) AMPK signaling activation was significantly increased in the SGZ and SVZ; and (iii) short-term but not long-term pharmacological inhibition of AMPK signaling could partially rescue hippocampal neurogenesis in the old brain. Taken together, these results indicate that AMPK is a critical mediator in the regulation of downstream processes for the age-related decline in hippocampal neurogenesis.