Bone morphogenetic protein 9 and insulin-like growth factor 2 modulate the cholinergic phenotype of the basal forebrain cholinergic system: relevance to aging and Alzheimer's disease
Burke, Rebecca M.
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The basal forebrain cholinergic neurons (BFCN), whose projections terminate in the cortex and hippocampus, are critically important for the processes of learning, memory, and attention. BFCN degeneration occurs with age and in Alzheimer's disease, and correlates with the cognitive decline observed in these states. Multiple stimuli, including growth factors, control the development, differentiation, and maintenance of the BFCN population. Specifically, bone morphogenetic protein 9 (BMP9/GDF2) increases acetylcholine (ACh) synthesis and choline acetyltransferase (CHAT) gene expression both in vivo and in vitro, and has therefore been characterized as a cholinergic differentiation and maintenance factor. Similarly, insulin-like growth factor 2 (IGF2) induces CHAT activity in an embryonic in vitro model and stimulates ACh release in rat hippocampal slices. Given the ability of BMP9 and IGF2 to promote the cholinergic phenotype, we explored the effects of a one-week intracerebroventricular infusion of BMP9 and IGF2 on the BFCN population in the adult wildtype rat and in the transgenic APPswe/PS1deltaE9 Alzheimer's disease mouse model. Our results revealed that IGF2 increased ACh levels in the frontal cortex of the adult rat by approximately 25%, and increased hippocampal nerve growth factor receptor-p75 protein levels, a marker of cholinergic neurons , by 40%. IGF2 increased the expression of hippocampal insulin-like growth factor 1, a cholinergic differentiation factor, by 26% in the adult rat. Similarly, BMP9 increased hippocampal CHAT protein expression in the 5-month old wildtype and APPswe/PS1deltaE9 mouse by 70% and 40%, respectively. BMP9 also prevented a transgene-mediated decrease in hippocampal CHAT protein levels in the 10-month old APPswe/PS1deltaE9 mouse. Furthermore, BMP9 increased the levels of nerve growth factor (NGF), a trophic factor for cholinergic neurons, in the 5-month old and 10-month old wildtype mouse hippocampus by 15% and 16%, respectively, and increased hippocampal NGF levels by 15% in the 10-month old APPswe/PS1deltaE9 mouse hippocampus. These results indicate that BMP9 and IGF2 promote the cholinergic phenotype and create an environment that is trophic for cholinergic neurons. These actions of IGF2 and BMP9 suggest that they may have therapeutic potential for the treatment of disease states that compromise cholinergic function.
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