CONTROL OF LIPID METABOLISM BY NGF/P75NTR SIGNALINGS IN NEURON-GLIA NETWORK: NOVEL TARGETS FOR NEURODEGENERATIVE DISEASES

Control of lipid metabolism by NGF/p75NTR signaling in neuron-glia network: novel targets for neurodegenerative diseases A prominent factor in cognitive abnormalities associated with various neurodegenerative diseases, including Alzheimer's Disease (AD) and Type 2 Diabetes (T2D), is the disruption of cholesterol metabolism in the neuron-glia network. Cholesterol dysmetabolism and associated brain insulin resistance have been linked to the cognitive decline produced by cholinergic deficits and astrocytosis in AD. The goal of the current research is to investigate the neurotrophic pathway in the protection of the neuro-glia network from the effect of the cholesterol metabolite 27-hydroxycholesterol (27-OH), the major circulating oxygenated cholesterol derivative, and a brain sensor of circulating cholesterol. In line, 27-OH is detected in high amount in the early stage AD brain, possibly contributing to cognitive deterioration. We discovered that 27-OH (1mM; 6-24 hours) inhibits NGF/TrkA signaling in NGF-responsive cholinergic neurons and human iPS-derived astrocytes by affecting the metabolism of amyloid precursor protein, and promotes the buildup of lipid rafts in the neuroglia network. We also found that 27-OH elicits nuclear translocation of the common neurotrophic receptor (p75NTR) in astrocytes before lipid rafts are loaded. On the other hand, both NGF (100ng/ml) and the selective p75NTR modulator LM11A-31 (100nM) can prevent p75NTR accumulation in the nucleus and subsequent lipid raft buildup, pinpointing that the NGF and p75NTR signalings play opposite roles in AD. Overall, NGF-based treatment and/or p75NTR-specific modulation are possible avenues to improve lipid metabolism and reduce cognitive decline in AD and T2D.