• alzheimer
• microglia
• mouse
• ngf
• trka

The Nerve Growth Factor (NGF) is crucial for the survival and differentiation of the nerve cells in the nervous system. To elicit its functions, NGF binds its Tropomyosin Kinase Receptor A (TrkA). The aim of my thesis was to explore the NGF-TrkA signaling in microglia. Indeed, (1) peripheral macrophages secrete and respond to NGF, and microglia represent the macrophages-like immune cells resident in the CNS. (2) Our lab identified neuroinflammation in an Alzheimer’s mouse model (AD11) producing anti-NGF antibody. (3) Microglia in vitro express TrkA receptors, and our lab showed that NGF has potent immunomodulatory properties via TrkA on microglia, steering them towards an anti-inflammatory and neuroprotective phenotype.
Considering this, an alteration of the NGF-TrkA signaling in microglia cells would be consistent with a non-neuroprotective phenotype.
To explore this hypothesis, I created a transgenic mouse model carrying a conditional TrkA knock-out in microglia. First, I confirmed that microglia in vivo express TrkA, via protein detection in microglia isolated from adult mouse brains. Then, I verified that the TrkA expression is efficiently dampened. Subsequently, I studied microglial density and 3D morphology, showing that knocking out TrkA in microglia leads to differences in microglial density in different brain areas if compared with controls. Moreover, TrkA-deprived microglia seem to show higher phagocytosis of spines, leading to a striking reduction of cortical spine density. Upon behavioral tests, transgenic mice have also revealed delayed motor learning, reduced exploratory behavior and reduced response to cold pain.
In conclusion, these results suggest the importance of TrkA signaling in pivotal roles of microglia cells, and calls for a closer look at their role both in health and disease.