Aging is frequently associated with a decline in multiple cognitive functions. In particular, the ability to form memories of recent events and assimilate new and complex information tends to diminish. Moreover, these cognitive defects are hallmarks of devastating, age-associated dementias such as Alzheimer's disease (AD). Due to their high prevalence and the lack of any effective therapies, the development of prevention measures and treatment strategies for these conditions constitutes one of the highest priorities of the biomedical sciences. The concept of utilizing juvenile protective factors for this purpose is an attractive on - however, it presents two central challenges: 1) the identification and characterization of a candidate factor, and 2) the utilization of its potential for therapeutic benefit. The proposed studies focus on a compelling candidate molecule - growth and differentiation factor 2 (GDF2), more commonly referred to as bone morphogenetic protein 9 (BMP9), and its actions on critical neuronal systems that underlie cognition. One of the key components of the neuronal circuitry necessary for learning, memory and attention is the innervation of the hippocampus and cerebral cortex by basal forebrain cholinergic neurons (BFCN), which provide modulatory input mediated by the neurotransmitter, acetylcholine (ACh). A decline in BFCN function and diminished cholinergic marker expression is apparent in aged humans and animal, in AD patients, and in animal models of AD. Thus, it has been postulated that dysfunction and/or degeneration of BFCN contributes to the memory deficits seen in advanced age and in AD. We have obtained evidence that BMP9 is a key differentiating factor for BFCN during development and, when infused intracerebroventricularly in mice with experimental injury to these neurons, prevents BFCN loss. Moreover, our preliminary data show that BMP9 infusion reverses the downregulation of BFCN markers seen in a transgenic mouse model of AD and ameliorates amyloidosis. These data indicate that BMP9 is sufficient to support BFCN differentiation and function in the adult brain; however we do not yet know to what extent BMP9 is necessary for cholinergic neuron biology.
In aim 1 this central question will be addressed by loss-of-function studies on Bmp9 knockout mice.
In aim 2 we will test the utility of BMP9 as a therapeutic agent for age-associated cognitive and BFCN dysfunction, with the focus on AD, using transgenic mouse models.
In aim 3, we will explore the hypothesis that BMP signaling may be abnormal in the brains of aging humans and AD patients, using post-mortem brain samples from a unique collection of cases with a thorough cognitive and histopathological assessment, available through the Framingham Heart Study.

Public Health Relevance

Aging is associated with a decline of multiple cognitive functions and this decline is particularly devastating in Alzheimer's disease (AD). We propose to provide a comprehensive characterization of the molecular phenotype of basal forebrain cholinergic neurons (BFCN) that are crucial for normal memory processing and that are vulnerable to deterioration in AD. We have identified bone morphogenetic protein 9 (BMP9) as a factor that protects BFCN from damage and we will determine if BMP9 has a similar efficacy in a mouse model of AD with the ultimate goal to develop a thorough understanding of BFCN biology and to develop growth- factor replacement strategies that could protect BFCN in people from age- and/or AD-evoked dysfunction.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1 (03))
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
Schools of Medicine
United States
Zip Code
Adams, Stephanie L; Benayoun, Laurent; Tilton, Kathy et al. (2018) Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer's Disease. J Alzheimers Dis 63:1433-1443
Tao, Qiushan; Zhu, Haihao; Chen, Xi et al. (2018) Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease. J Alzheimers Dis 62:597-609
Carreras, Isabel; Aytan, Nurgul; Mellott, Tiffany et al. (2018) Anxiety, neuroinflammation, cholinergic and GABAergic abnormalities are early markers of Gulf War illness in a mouse model of the disease. Brain Res 1681:34-43
Aytan, Nurgul; Choi, Ji-Kyung; Carreras, Isabel et al. (2018) Protective effects of 7,8-dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer's disease. Eur J Pharmacol 828:9-17
Adams, Stephanie L; Benayoun, Laurent; Tilton, Kathy et al. (2017) Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer's Disease Patients. J Alzheimers Dis 60:43-56
Blusztajn, Jan Krzysztof; Slack, Barbara E; Mellott, Tiffany J (2017) Neuroprotective Actions of Dietary Choline. Nutrients 9:
Mellott, Tiffany J; Huleatt, Olivia M; Shade, Bethany N et al. (2017) Perinatal Choline Supplementation Reduces Amyloidosis and Increases Choline Acetyltransferase Expression in the Hippocampus of the APPswePS1dE9 Alzheimer's Disease Model Mice. PLoS One 12:e0170450
Wang, Erming; Zhu, Haihao; Wang, Xiaofan et al. (2017) Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer's Disease Mouse Model. J Alzheimers Dis 56:47-61
Mathew, Rebecca S; Mullan, Hillary; Blusztajn, Jan Krzysztof et al. (2016) Comment on ""Multiple repressive mechanisms in the hippocampus during memory formation"". Science 353:453
Blusztajn, Jan Krzysztof; Rinnofner, Jasmine (2016) Intrinsic Cholinergic Neurons in the Hippocampus: Fact or Artifact? Front Synaptic Neurosci 8:6