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, though 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.

A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood

“…Some of the broadly functioning inhibitory culprits of the aged systemic and local niches of stem cells have been defined, for example, TGF-beta1, osteopontin and the secretome of senescent cells783031. While it is unlikely that TGF-beta1 crosses the blood–brain barrier (BBB) and heterochronic blood transfusion does not significantly change TGF-beta 1 levels in muscle, excessively high TGF-beta1 (as found locally in tissues and in circulation in old mice and humans) can promote vascular changes leading to the leakiness of the BBB, as well as inhibit neurogenesis indirectly via inflammation and contribute to broad (other than brain) tissue pathologies12345678.…”

Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis

“…Importantly, we found that these changes in NSC behaviour arise early (in mice as young as 1-month of age; Figure 1I) and take place mostly during the first 12 months of life. These changes are therefore distinct from ageing-associated pathological changes that lead to NSC dysfunction (Ibrayeva et al, 2019;Leeman et al, 2018;Miranda et al, 2012;Seib et al, 2013;Yousef et al, 2015) Resting NSCs increasingly contribute to the proliferative NSC pool…”

A morphology independent approach for identifying dividing adult neural stem cells in the mouse hippocampus

“…Dividing AH‐NSCs and IPs are frequently found together in clusters (Hodge et al, ), and it therefore becomes difficult to determine to which cell a radial AH‐NSC process is linked. Finally, there is a lack of standardization as to which radial markers are appropriate to use when identifying dividing AH‐NSCs, demonstrated by the variety employed in many studies (Gulbins et al, ; Li et al, ; Martynoga et al, ; Andersen et al, ; Kandasamy et al, ; Andreu et al, ; Nicola et al, ; Yousef et al, ). Together, these issues pose great challenges to the interpretation and comparison of the many studies in this field.…”