ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age

Rationale: Degeneration of basal forebrain cholinergic neurons (BFCNs) plays an important role in aging and Alzheimer's disease (AD) pathology. This degeneration may be a result of disrupted nerve growth factor (NGF) signaling. Aged rats have memory deficits, BFCN degeneration, and disrupted NGF signaling. Objective: In this study we identify a rapid NGF signaling pathway in BFCNs and the second messenger system associated with that signaling. We also identify age-dependent alterations in this signaling pathway. Materials and methods: After cognitive assessment using the Morris water maze, rats were given an intra-hippocampal NGF injection. Basal forebrain immunohistochemical analysis, confocal microscopy, and inhibitor studies were performed. Results: An increase in immunoreactivity for the NGF receptor TrkA was found in cell bodies of BFCNs 15 min and 1 h post-NGF injection. Immunohistochemistry studies with phospho-ERK and phospho-AKT antibodies showed that this rapid signaling occurred through MAP kinase, but not PI-3 kinase pathways. MAPK inhibitor studies attenuated the NGF-induced effects. Both TrkA and phospho-ERK (extracellular signal-regulated kinase) immunoreactivities were diminished in aged rats and phospho-ERK immunoreactivity-correlated with aged rat performance in the Morris water maze. Conclusions: Rapid NGF signaling likely occurs in the rat CNS through the MAPK signaling pathway. This rapid signaling pathway is diminished in aged rats compared to young ones and may contribute to memory deficits observed in aged rats. As cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, ERK-related dysfunction may be relevant in human conditions as well.