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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

NGFR-p75, TrkA and NGF protein levels in hippocampus (HPP).Mice were treated as in Fig. 4. NGFR-p75 (** p<0.01 BMP vs PBS on the same side) and TrkA (significant treatment effect of BMP9 by two-way ANOVA, p<0.05) were measured by Western blot (top panel) and the data quantified as in Fig. 5. NGF was measured by ELISA (* p<0.05, ** p<0.01 BMP9 vs PBS on the same side).
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pone-0021166-g006: NGFR-p75, TrkA and NGF protein levels in hippocampus (HPP).Mice were treated as in Fig. 4. NGFR-p75 (** p<0.01 BMP vs PBS on the same side) and TrkA (significant treatment effect of BMP9 by two-way ANOVA, p<0.05) were measured by Western blot (top panel) and the data quantified as in Fig. 5. NGF was measured by ELISA (* p<0.05, ** p<0.01 BMP9 vs PBS on the same side).

Mentions: It is well established that basal forebrain cholinergic neurons benefit from hippocampal NGF as a trophic factor for survival and maintenance of their cholinergic phenotype [9]–[12]. We have recently shown that BMP9 can induce NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons [21]. To determine whether BMP9 had an effect on NGF content in the hippocampus of fimbria-fornix lesioned mice and, perhaps, explain some of our data described above, we analyzed the levels of NGF protein in the hippocampus of these mice by ELISA. NGF levels were increased in the hippocampus of BMP9 treated mice by 47% and 61% on the lesioned and unlesioned side, respectively, compared to the corresponding levels in the hippocampus of PBS infused control animals (Fig. 6).


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

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

NGFR-p75, TrkA and NGF protein levels in hippocampus (HPP).Mice were treated as in Fig. 4. NGFR-p75 (** p<0.01 BMP vs PBS on the same side) and TrkA (significant treatment effect of BMP9 by two-way ANOVA, p<0.05) were measured by Western blot (top panel) and the data quantified as in Fig. 5. NGF was measured by ELISA (* p<0.05, ** p<0.01 BMP9 vs PBS on the same side).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0021166-g006: NGFR-p75, TrkA and NGF protein levels in hippocampus (HPP).Mice were treated as in Fig. 4. NGFR-p75 (** p<0.01 BMP vs PBS on the same side) and TrkA (significant treatment effect of BMP9 by two-way ANOVA, p<0.05) were measured by Western blot (top panel) and the data quantified as in Fig. 5. NGF was measured by ELISA (* p<0.05, ** p<0.01 BMP9 vs PBS on the same side).
Mentions: It is well established that basal forebrain cholinergic neurons benefit from hippocampal NGF as a trophic factor for survival and maintenance of their cholinergic phenotype [9]–[12]. We have recently shown that BMP9 can induce NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons [21]. To determine whether BMP9 had an effect on NGF content in the hippocampus of fimbria-fornix lesioned mice and, perhaps, explain some of our data described above, we analyzed the levels of NGF protein in the hippocampus of these mice by ELISA. NGF levels were increased in the hippocampus of BMP9 treated mice by 47% and 61% on the lesioned and unlesioned side, respectively, compared to the corresponding levels in the hippocampus of PBS infused control animals (Fig. 6).

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