Nerve growth factor influences microglial activity via TrkA

The Nerve Growth Factor (NGF) has been linked to Alzheimer’s disease (AD) due to its survival-promoting activity on cholinergic neurons in the basal forebrain, whose demise contributes to cognitive decline in AD. Related to that, we demonstrated that intranasal administration of a painless NGF (hNGFp) displays a wide beneficial effect in the brain of an AD mouse model (5xFAD) by rescuing not only cholinergic defects, but also cortical and hippocampal beta-amyloid depositions and memory alterations. Since hNGFp only acts on Tropomyosin receptor kinase A (TrkA), and non-cholinergic neurons do not express TrkA, we hypothesized that this broad neuroprotective activity of hNGFp would be mediated by other TrkA-expressing cells, such as microglia, which is positively modulated by the treatment. Indeed, we recently showed that NGF has potent positive immunomodulatory properties via TrkA on microglia in vitro and hNGFp acts beneficially on microglia in a mouse model of Rett Syndrome. These findings triggered an important question: what is the physiological function of microglial TrkA in vivo? To explore this, we generated a novel transgenic mouse model allowing specific TrkA deletion in microglia. Here, we report that TrkA-KO microglia show altered morphology, higher phagocytosis of spines and alterations in branch motility, both in culture and in vivo. Additionally, transgenic mice revealed mild recognition memory deficits. In conclusion, these results suggest the importance of microglial TrkA signaling in modulating pivotal homeostatic features of these cells, and calls for a closer look at its role both in physiological and pathological conditions, as in AD.