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.

Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment

“…BMP4 overexpression significantly reduced the total number of proliferating cells as well as the number of proliferating progenitor cells in the DG compared to control mice, consistent with previous studies showing that BMP signaling causes neural stem and progenitor cells to exit cell cycle. 15, 20 Despite the reduction in hippocampal proliferation in BMP4-overexpressing mice, we did not observe an increase in depression-like behavior in these mice, which is consistent with previous studies which have shown that inhibiting hippocampal neurogenesis is not sufficient to induce a depression-like phenotype. 9, 38–40 Chronic stress produces a decrease in hippocampal neurogenesis, 41–43 raising the possibility that ablation of neurogenesis may increase the susceptibility to the behavioral effects of stress.…”

“…At 16 days post injection, BMPRII ablation significantly increased the number of newborn neurons as assessed by the number of ZG+ cells expressing the neuronal marker NeuN (Figure 4b, c; WT 24600±2791 n=8, BMPRII KO 36424±4547 n=8, p<0.05), consistent with previous studies demonstrating enhanced maturation of NPCs into neurons in the absence of BMP signaling. 15, 20 Behavioral analysis on the TST demonstrated that ablation of BMPRII increased latency to immobility (Figure 4d; WT 54.08±5.84 n=8, BMPRII KO 79.73±9.78 n=8, p<0.05) and decreased the total time immobile (Figure 4e; WT 165±8.2 n=8, BMPRII KO 108.6±8.8 n=8, p<0.001). In the EZM, BMPRII ablation produced a trend towards an increase in the percentage of time spent in the open arms (Figure 4f; WT 29.42±2.88 n=8, BMPRII KO 36.17±2.12 n=8, p=0.08).…”

“…15 Further, noggin-overexpressing mice perform markedly better on tests of hippocampus-dependent cognition. 19, 20 Since BMP signaling has such a major regulatory influence on neurogenesis and cognition, we asked whether BMP signaling regulates antidepressant activity. Here we demonstrate that BMP signaling is inhibited by fluoxetine, and prevention of this decrease via overexpression of BMP4 blocks effects of fluoxetine treatment on hippocampal neural progenitor cell proliferation and behavior.…”

“…15, 18 Inhibition of BMP signaling in mice results in improved performance on hippocampus-dependent cognitive tasks 19 and can reverse some cognitive deficits associated with aging. 20 While many exogenous factors in the DG stimulate hippocampal neurogenesis, 21 BMP signaling conversely diminishes neurogenesis and provides a mechanism for allostatic control of the neurogenic process.…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…BMP-2, BMP-4, and BMP-7 are expressed in the SVZ and promote astroglial lineage commitment, whereas noggin suppresses it (Lim et al 2000;Colak et al 2008). In the SGZ, exogenous expression of noggin and BMP-4, or inactivation of either BMPRIA or Smad4 show the role of BMP signaling in the regulation of quiescence and activation of neural stem cells (Bonaguidi et al 2008;Colak et al 2008;Mira et al 2010;Bond et al 2014;Meyers et al 2016). …”