title: Age-Associated Increase in BMP Signaling Inhibits Hippocampal Neurogenesis.
abstract: Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, although evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone morphogenetic protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline.
authors.affiliation: Department of Molecular and Cell Biology; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Hanadie
authors.initials: H
authors.lastname: Yousef
authors.forename: Adam
authors.initials: A
authors.lastname: Morgenthaler
authors.forename: Christina
authors.initials: C
authors.lastname: Schlesinger
authors.forename: Lukasz
authors.initials: L
authors.lastname: Bugaj
authors.forename: Irina M
authors.initials: IM
authors.lastname: Conboy
authors.forename: David V
authors.initials: DV
authors.lastname: Schaffer
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; C045073:Cre recombinase; D019426:Integrases
keywords: Adult stem cells; Aging; BMP signaling; Neural stem cell; Neurogenesis; Proliferation; Stem cell-microenvironment interactions