Heme-Oxygenase I and PCG-1α Regulate Mitochondrial Biogenesis via Microglial Activation of Alpha7 Nicotinic Acetylcholine Receptors Using PNU282987.

Aims: A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which lead to low-energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases (NDDs). Glial cells are important for brain homeostasis, and microglia controls the central immune response, where alpha 7 acetylcholine nicotinic receptors (nAChR) seem to play a pivotal role; however, little is known about the effects of this receptor in metabolism. Therefore, the aim of this study was to evaluate if glial mitochondrial energetics could be regulated through alpha 7 nAChR. Results: Primary glial cultures treated with the alpha 7 nicotinic agonist PNU282987 increased theirmitochondrialmass and their mitochondrial oxygen consumption without increasing oxidative stress; these changes were abolished when nuclear erythroid 2-related factor 2 (Nrf2) was absent, heme oxygenase-1 (HO-1) was inhibited, or peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1 alpha) was silenced. More specifically, microglia of animals treated intraperitoneally with the alpha 7 nAChR agonist PNU282987 (10mg/kg) showed a significant increase in mitochondrial mass. Interestingly, LysM(cre)-Hmox1(Delta/Delta) and PGC-1 alpha(-/-) animals showed lower microglial mitochondrial levels and treatment with PNU282987 did not produce effects on mitochondrial levels. Innovation: Increases in microglial mitochondrial mass and metabolism can be achieved via alpha 7 nAChR by a mechanism that implicates Nrf2, HO-1, and PGC-1 alpha. This signaling pathway could open a new strategy for the treatment of NDDs, such as Alzheimer's, characterized by a reduction of cholinergic markers. Conclusion: alpha 7 nAChR signaling increases glial mitochondrial mass, both in vitro and in vivo, via HO-1 and PCG-1 alpha. These effects could be of potential benefit in the context of NDDs.