Juvenile trophic factors for the prevention and treatment of hippocampal aging

Summary

Principal Investigator: Jan Blusztajn
Abstract: DESCRIPTION (provided by applicant): Aging is associated with a decline of multiple cognitive functions. In particular, the ability to form memories of recent events and learn new complex information tends to diminish. The hippocampus is critical for the establishment of new memories, and there is evidence from studies in animals and humans that advanced age causes structural and neurochemical changes in the hippocampus that result in its functional impairment, leading to cognitive deficits. One of the key components of the hippocampal neuronal circuitry that is necessary for learning and memory is its innervation by the septo-hippocampal pathway that provides a modulatory input mediated by the neurotransmitter, acetylcholine (ACh). This cholinergic innervations develops during the first two postnatal weeks in rats and mice but its function declines in aging brain. Unlike most other brain regions, the hippocampus is characterized by a life-long capacity for neurogenesis - an outcome of divisions of the dentate gyrus neuronal precursor cells whose progeny can differentiate into functional granule neurons integrated into the granule cell layer. This neurogenic activity is high in the young animal but declines with age. While the role of adult neurogenesis remains to be understood, there is evidence that it is necessary for normal hippocampal function and that impaired neurogenesis in aged brain correlates with cognitive decline. Hippocampal structure and function are regulated by trophic and differentiating factors. These molecules modulate the establishment and maintenance of the septohippocampal cholinergic pathway and hippocampal neurogenic activity under normal conditions and in response to disease and/or injury. The expression of some of these trophic factors is particularly high during early postnatal maturation of the hippocampus and low in the adult. We have identified two such juvenile factors, bone morphogenetic protein 9 (BMP9) and insulin-like growth factor 2 (IGF2). The overall goal of the proposed studies is to test the hypothesis that administration of these putative juvenile protective factors (BMP9 or IGF2) to the brain of aging Fischer 344 rats will prevent the decline or cause a recovery of hippocampal function as determined by assays of cholinergic markers, neurogenesis, and cognitive performance. We will 1) verify that BMP9 and IGF2 function as juvenile trophic factors in postnatal development of the hippocampus by reducing their levels during the critical postnatal periods with intracerebroventricular (icv) administration of neutralizing antibodies against these factors, and 2) determine if the icv administration of BMP9 or IGF2 to aged rats improves hippocampal function. The ultimate goal of our studies is to relate our results to the age-associated changes in memory in humans, and to develop juvenile trophic-factor replacement strategies which could benefit people. Aging is associated with a decline of multiple cognitive functions. We have identified two proteins, bone morphogenetic protein 9 (BMP9) and insulin-like growth factor 2 (IGF2) that are abundant in juvenile brain but decline with brain's maturation and we propose that administration of these putative juvenile protective factors (BMP9 or IGF2) to the brain will prevent the decline or cause a recovery of brain function associated with aging, using old rats as a model. The ultimate goal of our studies is to relate our results to the age-associated changes in memory in humans, and to develop juvenile growth-factor replacement strategies that could benefit people.
Funding Period: ----------------2008 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer's disease
    Rebecca M Burke
    Department of Pathology and Laboratory Medicine, Department of Anatomy and Neurobiology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118
    Proc Natl Acad Sci U S A 110:19567-72. 2013
  2. pmc IGF2 ameliorates amyloidosis, increases cholinergic marker expression and raises BMP9 and neurotrophin levels in the hippocampus of the APPswePS1dE9 Alzheimer's disease model mice
    Tiffany J Mellott
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
    PLoS ONE 9:e94287. 2014
  3. pmc BMP9 (bone morphogenetic protein 9) induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons
    Aletta C Schnitzler
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Neurosci 30:8221-8. 2010
  4. pmc Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin
    Robyn M Carey
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
    BMC Cell Biol 12:20. 2011
  5. pmc BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype
    Ignacio Lopez-Coviella
    Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America
    PLoS ONE 6:e21166. 2011

Scientific Experts

  • Jan Blusztajn
  • Robyn M Carey
  • Tiffany J Mellott
  • Rebecca M Burke
  • Ignacio Lopez-Coviella
  • Aletta C Schnitzler
  • Sarah M Pender
  • Erika A Langley
  • Tarik F Haydar
  • Timothy A Norman
  • Susan E Leeman
  • Barbara E Slack
  • Yvonne N Tallini
  • Maximillian T Follettie
  • Michael I Kotlikoff

Detail Information

Publications5

  1. pmc BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer's disease
    Rebecca M Burke
    Department of Pathology and Laboratory Medicine, Department of Anatomy and Neurobiology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118
    Proc Natl Acad Sci U S A 110:19567-72. 2013
    ....
  2. pmc IGF2 ameliorates amyloidosis, increases cholinergic marker expression and raises BMP9 and neurotrophin levels in the hippocampus of the APPswePS1dE9 Alzheimer's disease model mice
    Tiffany J Mellott
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
    PLoS ONE 9:e94287. 2014
    ..These data show that IGF2 administration is effective in reversing and preventing several pathophysiologic processes associated with AD and suggest that IGF2 may constitute a therapeutic target for AD. ..
  3. pmc BMP9 (bone morphogenetic protein 9) induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons
    Aletta C Schnitzler
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Neurosci 30:8221-8. 2010
    ..The data suggest an autocrine/paracrine role for NGF in the development and/or maintenance of BFCN and imply that the stimulation of NGF production and release contributes to the cholinergic-supportive properties of BMP9...
  4. pmc Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin
    Robyn M Carey
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
    BMC Cell Biol 12:20. 2011
    ..This was accompanied by a reduction in Aβ generation. In the present study, we investigated whether surface expression of the α-secretase ADAM (a disintegrin and metalloprotease)10 is also regulated by dynamin-dependent endocytosis...
  5. pmc BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype
    Ignacio Lopez-Coviella
    Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America
    PLoS ONE 6:e21166. 2011
    ..Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro...