Abstract
BackgroundCholinergic projection from the septum to the hippocampus is crucial for normal cognitive function and degeneration of cells and nerve fibers within the septohippocampal pathway contributes to the pathophysiology of Alzheimer's disease. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro.Methodology/Principal FindingsTo determine whether BMP9 could protect the adult cholinergic septohippocampal pathway from axotomy-evoked loss of the cholinergic phenotype, we performed unilateral fimbria-fornix transection in mice and treated them with a continuous intracerebroventricular infusion of BMP9 for six days. The number of choline acetyltransferase (CHAT)-positive cells was reduced by 50% in the medial septal nucleus ipsilateral to the lesion as compared to the intact, contralateral side, and BMP9 infusion prevented this loss in a dose-dependent manner. Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi. In addition, BMP9 infusion reduced bilaterally hippocampal levels of basic FGF (FGF2) protein.Conclusions/SignificanceThese data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells.
Highlights
The cholinergic neurons of the medial septal nucleus send their axons to the hippocampus providing it with a robust modulatory input mediated by their neurotransmitter, acetylcholine (ACh)
In the present study we found that intracerebroventricular (ICV) infusion of BMP9 prevents the loss of cholinergic neurons, as defined by their expression of the ACh-synthesizing enzyme choline acetyltransferase (CHAT), in the septum following unilateral fimbria-fornix transection in mice and upregulates the expression of hippocampal NGF and its receptors NGFR-p75 and TRKA (NTRK1)
Sparing of the cholinergic neurons was evident with increasing doses of BMP9, and there was little or no loss of these neurons in animals receiving 15 and 38 ng/h of BMP9 (Figs. 2 and 3), indicating that BMP9 was highly effective in preventing the loss of CHAT-positive neurons whose axons had been transected
Summary
The cholinergic neurons of the medial septal nucleus send their axons to the hippocampus providing it with a robust modulatory input mediated by their neurotransmitter, acetylcholine (ACh). Degeneration and/ or malfunction of the septohippocampal cholinergic system is thought to contribute to cognitive decline of old age and to memory loss characteristic of Alzheimer’s disease [4]. Lesions of this pathway in laboratory animals impair learning and memory in various tests [5]. In an effort to correct similar deficits in AD, a number of therapeutic approaches have been undertaken to increase the levels of brain ACh in humans Some of these strategies are based on the use of acetylcholinesterase inhibitors, to reduce the rate of degradation of ACh in brain [8]. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro
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