title: Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition.
abstract: Aging is associated with decreased neurogenesis in the hippocampus and diminished hippocampus-dependent cognitive functions. Expression of bone morphogenetic protein 4 (BMP4) increases with age by more than 10-fold in the mouse dentate gyrus while levels of the BMP inhibitor, noggin, decrease. This results in a profound 30-fold increase in phosphorylated-SMAD1/5/8, the effector of canonical BMP signaling. Just as observed in mice, a profound increase in expression of BMP4 is observed in the dentate gyrus of humans with no known cognitive abnormalities. Inhibition of BMP signaling either by overexpression of noggin or transgenic manipulation not only increases neurogenesis in aging mice, but remarkably, is associated with a rescue of cognitive deficits to levels comparable to young mice. Additive benefits are observed when combining inhibition of BMP signaling and environmental enrichment. These findings indicate that increased BMP signaling contributes significantly to impairments in neurogenesis and to cognitive decline associated with aging, and identify this pathway as a potential druggable target for reversing age-related changes in cognition.
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA. Electronic address: emilymeyers2015@u.northwestern.edu.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Meyers
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Gobeske
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Bond
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Jarrett
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Chian-Yu
authors.initials: CY
authors.lastname: Peng
authors.affiliation: Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Kessler
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology / Q000502:physiology / Q000523:psychology*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003071:Cognition; D003072:Cognition Disorders / Q000235:genetics / Q000628:therapy; D018891:Dentate Gyrus / Q000378:metabolism; D015870:Gene Expression; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D055495:Neurogenesis; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse
keywords: Aging; Dentate gyrus; Environmental enrichment; Neural stem cell; Novel object recognition
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