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BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype.

Lopez-Coviella I, Mellott TJ, Schnitzler AC, Blusztajn JK - PLoS ONE (2011)

Bottom Line: Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro.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.These 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT

Background: Cholinergic 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 findings: To 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/significance: These 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.

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Related in: MedlinePlus

Acetylcholine content in hippocampus measured by HPLC in mice with a unilateral septohippocampal lesion following seven days of constant intracerebroventricular infusion of vehicle or 8 ng/h of BMP9.Note a significant (*p<0.01; 72%) sparing of the loss of hippocampal ACh content in lesioned mice receiving BMP9.
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pone-0021166-g004: Acetylcholine content in hippocampus measured by HPLC in mice with a unilateral septohippocampal lesion following seven days of constant intracerebroventricular infusion of vehicle or 8 ng/h of BMP9.Note a significant (*p<0.01; 72%) sparing of the loss of hippocampal ACh content in lesioned mice receiving BMP9.

Mentions: To determine whether BMP9 could affect ACh levels in the hippocampus, we performed similar experiments in mice with fimbria-fornix transections using a small, yet close to a fully effective dose of BMP9 identified above (8 ng/h, via a 6-day ICV infusion; Fig. 3), and measured ACh content in both lesioned and unlesioned hippocampi. Seven days after the lesion, ACh content in the hippocampus ipsilateral to the lesion was reduced to 34% compared to the unlesioned side in mice that had been infused with PBS, whereas ACh levels in the hippocampus ipsilateral to the lesion in mice infused with BMP9 were reduced to only 72% (Fig. 4). Thus, BMP9 treatment significantly (p<0.01) prevented the reduction in ACh levels in the lesioned hippocampus when compared to untreated animals. The magnitude of this effect was the same regardless of whether ACh content was expressed per hippocampus, or per mg of protein.


BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype.

Lopez-Coviella I, Mellott TJ, Schnitzler AC, Blusztajn JK - PLoS ONE (2011)

Acetylcholine content in hippocampus measured by HPLC in mice with a unilateral septohippocampal lesion following seven days of constant intracerebroventricular infusion of vehicle or 8 ng/h of BMP9.Note a significant (*p<0.01; 72%) sparing of the loss of hippocampal ACh content in lesioned mice receiving BMP9.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3113905&req=5

pone-0021166-g004: Acetylcholine content in hippocampus measured by HPLC in mice with a unilateral septohippocampal lesion following seven days of constant intracerebroventricular infusion of vehicle or 8 ng/h of BMP9.Note a significant (*p<0.01; 72%) sparing of the loss of hippocampal ACh content in lesioned mice receiving BMP9.
Mentions: To determine whether BMP9 could affect ACh levels in the hippocampus, we performed similar experiments in mice with fimbria-fornix transections using a small, yet close to a fully effective dose of BMP9 identified above (8 ng/h, via a 6-day ICV infusion; Fig. 3), and measured ACh content in both lesioned and unlesioned hippocampi. Seven days after the lesion, ACh content in the hippocampus ipsilateral to the lesion was reduced to 34% compared to the unlesioned side in mice that had been infused with PBS, whereas ACh levels in the hippocampus ipsilateral to the lesion in mice infused with BMP9 were reduced to only 72% (Fig. 4). Thus, BMP9 treatment significantly (p<0.01) prevented the reduction in ACh levels in the lesioned hippocampus when compared to untreated animals. The magnitude of this effect was the same regardless of whether ACh content was expressed per hippocampus, or per mg of protein.

Bottom Line: Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro.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.These 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT

Background: Cholinergic 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 findings: To 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/significance: These 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.

Show MeSH
Related in: MedlinePlus