BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer’s disease
Open accessAbstract
Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aβ42-positive amyloid plaques in the hippocampus and cerebral cortex of 5- and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aβ42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.
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BMP9, MyD88, and mTOR were previously involved in restricting amyloidosis, microglial response to pathogens, and pro-inflammatory microglia.
“which were previously involved in restricting amyloidosis56, microglial response to pathogens57, and pro-inflammatory microglia58”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [56]
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Regulation of Bone Morphogenetic Protein 9 (BMP9) by Redox-dependent Proteolysis
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“Administration of BMP9 was effective in reversing the A 42 amyloid plaque burden and reversing cholinergic neuron abnormalities in a mouse model of Alzheimer disease (51).”
BackgroundWhole-Brain Monosynaptic Afferent Inputs to Basal Forebrain Cholinergic System
Hu, R. K., Jin, S., He, X., Xu, F., & Hu, J. (2016) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2016.00098 · Cited by 46 · see citing works
Nanoneuromedicine for management of neurodegenerative disorder
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“Growth factors (GFs) like insulin-like growth factor (IGF-1/IGF-2) [75,76], bone morphogenetic proteins (BMPs) [71,77,78], basic fibroblast growth factor (bFGF) [79–81] and glialderived neurotrophic factor, GDNF [82], neurotrophins (nerve growth factors, NGF) [83–85]; and brain-derived neurotrophic factor (BDNF) [86,8…”
BackgroundRapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains
Kienast, Y., Jucknischke, U., Scheiblich, S., Thier, M., de Wouters, M., Haas, A. K., Lehmann, C., Brand, V. B., Bernicke, D., Honold, K., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.680009 · Cited by 42 · see citing works
“Administration of BMP9 holds therapeutic potential in bone and cartilage defects and neurodegenerative disease (36, 37).”
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Carreras, I., Aytan, N., Mellott, T. J., Choi, J., Lehar, M., Crabtree, L., Leite‐Morris, K. A., Jenkins, B. G., Blusztajn, J. K., & Dedeoglu, A. (2017) · Brain Research · doi:10.1016/j.brainres.2017.12.030 · Cited by 36 · see citing works
Self-citationNetwork-driven plasma proteomics expose molecular changes in the Alzheimer’s brain
Jaeger, P. A., Lucin, K. M., Britschgi, M., Vardarajan, B. N., Huang, R.-P., Kirby, E. D., Abbey, R. J., Boeve, B. F., Boxer, A. L., Farrer, L. A., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0095-2 · Cited by 34 · see citing works
“While TGFβ and TGFβ-receptor signaling has been studied extensively in the context of AD and neuroinflammation [25, 26], and BMP9/GDF2 has been identified as a regulator of cholinergic neuronal development [27], Activin receptor signaling and GDFs have not been studied in AD.”
BackgroundGrowth factor treatment to overcome Alzheimer's dysfunctional signaling
Lauzon, M.-A., Daviau, A., Marcos, B., & Faucheux, N. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.02.018 · Cited by 30 · see citing works
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“The use of growth factors AC CE PT ED M AN US CR IP T (GFs), especially bone morphogenetic 9 (BMP-9) naturally present in the healthy brain, might act on one or more therapeutic targets of AD (Burke et al., 2013; Lopez-Coviella et al., 2000; Mellott, Langley et al., 2014; Schnitzler et al., 2010).”
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A systems biology approach for studying neurodegenerative diseases
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Peptides Derived from Growth Factors to Treat Alzheimer’s Disease
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“↑ IGF-1 levels in 5 months APP.PS1/CHGFP Animal: APP/PS1 mice (7 months) Improve spatial and associative learning and memory (Morris water maze, contextual fear conditioning test) [107] ↓ Aβ levels and number of plaques in AD model Treatment: intranasal delivery of 50 ng/g/d for 30 days ↓ Hyperphosphorylated tau in th…”
BackgroundInfluentialFitzgerald, G. S., Chuchta, T. G., & McNay, E. C. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14160 · Cited by 22 · see citing works
Whole-Brain Mapping of Monosynaptic Afferent Inputs to Cortical CRH Neurons
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“Received: 12 December 2016 Accepted: 27 January 2017 Published: 08 February 2017 Citation: Wang Z, Xiong L, Wan W, Duan L, Bai X and Zu H (2017) Intranasal BMP9 Ameliorates Alzheimer Disease-Like Pathology and Cognitive Deficits in APP/PS1 Transgenic Mice.”
BackgroundInfluentialIntrinsic Cholinergic Neurons in the Hippocampus: Fact or Artifact?
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“The intraventricular infusion of IGF-II in the AD model mice reduces the accumulation of amyloid plaques in the HP and cerebral cortex, which can ameliorate learning and memory in AD model mice [22,23].”
BackgroundNew treatment modalities in Alzheimer's disease
Köseoğlu, E. (2019) · World Journal of Clinical Cases · doi:10.12998/wjcc.v7.i14.1764 · Cited by 17 · see citing works
The potential regulatory role of BMP9 in inflammatory responses
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American Ginseng for the Treatment of Alzheimer’s Disease: A Review
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“It has been reported that BMP9 plays a role in promoting cutaneous wound healing [18], regulating glucose metabolism [19, 20], improving amyloidosis, cholinergic deficiency, pathology, and cognitive deficiencies in a mouse model of Alzheimer’s disease [21, 22].”
BackgroundGenetically-Predicted Adult Height and Alzheimer’s Disease
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“Members of the bone morphogenetic protein family of growth factors have been implicated as crucial modulators of neurogenesis in the adult hippocampus [25, 26] and have been demonstrated to affect amyloid-β-induced neurotoxicity [27, 28] and amyloid plaque burden [29].”
BackgroundCholinergic Reinforcement Signaling Is Impaired by Amyloidosis Prior to Its Synaptic Loss
Allard, S., & Shuler, M. G. H. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.0967-23.2023 · Cited by 11 · see citing works
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“As another reason for the negative results of the behavioral tests, ChAT activity might be sufficient under normal circumstances [35] because of other cholinergic regulators, such as nerve growth factor [36,37], TrkA and p75NTR NGF receptors [38–40], brain-derived neurotrophic factor [41], and neurtrophin-3/4 [42].”
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“Moreover,wesubsequentlyshowed thatBMP9infusionreversesthedownregulationof BFCNmarkersinatransgenicmousemodelofAD, ameliorateshippocampalamyloidosis,andincreases theexpressionofseveralgrowthfactors(NGF,NT3, andIGF1)[22].”
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The Value of the Object Recognition Paradigm in Investigating Animal Models of Alzheimer's Disease
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“Therefore, research efforts have been made to maintain cholinergic neurons from the point of view of neurotrophic factors, such as NGF [19], brain-derived neurotrophic factor [36], and bone morphogenetic protein-9 [37].”
BackgroundRegenerative nanomedicine applications for neurodegenerative diseases of central nervous system
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Growth factors and their receptors
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“In the case of ALK1 dysfunction in early AD, these strategies could include treatment with agonists (Burke et al. 2013; Long et al. 2015; Wang et al. 2017; Akla et al. 2018) or with drugs that enhance ALK1-mediated signaling (Ruiz et al.”
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“Exogenous BMP9 administration improves cognition and reduces amyloid pathology in AD mouse models, indicating its proneurogenic and neuroprotective effects [23].”
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- Authors
- Burke, R. M., Norman, T. A., Haydar, T. F., Slack, B. E., Leeman, S. E., Blusztajn, J. K., & Mellott, T. J.
- Affiliations
- Boston University (US)
- Department of Pathology and Laboratory Medicine,
- Department of Anatomy and Neurobiology, and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-11-11
- Volume
- 110
- Issue
- 48
- Pages
- 19567-19572
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3845152
- OpenAlex
- W2068348032
- Cited by
- 59
- References
- 66
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 7 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 6 · 2017: 9 · 2016: 7 · 2015: 6 · 2014: 2
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG032709, Z01AG000015, NIH T32AG00015, AG032709)
- National Institute of Neurological Disorders and Stroke (R01NS051852, NS076503, R01NS076503, NS051852)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- BMP9, Alzheimer's disease, amyloid plaques, amyloid-beta 42, cholinergic neurons, cholinergic deficit, APP/PS1 mice, intracerebroventricular infusion, choline acetyltransferase, neurotrophic factors, nerve growth factor, neurotrophin-3, insulin-like growth factor I, p75NGFR, hippocampus, therapeutic target
- MeSH terms
- Alzheimer Disease, Amyloidosis, Analysis of Variance, Animals, Female, Immunoassay, Immunohistochemistry, Male, Microscopy, Fluorescence, Immunoblotting, Mice, Growth Differentiation Factor 2, Cholinergic Neurons
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