Age-related decline in BubR1 impairs adult hippocampal neurogenesis

Abstract

Aging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age-related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging-related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age-related cognitive deficits.

Keywords: Adult neurogenesis; aging; bubR1; dendrite morphogenesis; hippocampus; progeroid mouse model.

Figure 1

Impaired neural progenitor proliferation and neurogenesis in adult BubR1 ^H/H mice. (A) BubR1 expression as determined by qRT–PCR. Values are normalized to 2‐month‐old mice. One‐way ANOVA with Bonferroni post hoc test. (B) Sample images of MCM2 and DAPI staining and quantification. Scale bars: 100 μm. (C) Sample images of MCM2, DCX, and DAPI staining and quantification. Scale bar: 50 μm. White arrows point to MCM2⁺ DCX ⁺ neuroblasts, and yellow arrows point to MCM2⁺ DCX ⁻ neural progenitors. (D) BubR1 ^H/H mice show age‐dependent reduction in DCX ⁺ immature neurons. (E) Sample images of EdU and NeuN staining and quantification. Scale bar: 50 μm. All values represent mean ± SEM. **: P < 0.01, ***: P < 0.001, unpaired t‐test unless noted otherwise. Number associated with bar graphs indicates the number of mice examined.

Figure 2

Deficits in neuronal maturation in adult BubR1 ^H/H mice. (A) BubR1 expression in postmitotic neurons in vitro. Sample images of MAP2 (a mature neuron marker), BubR1, and DAPI staining in differentiated postmitotic neurons derived from hippocampal NSCs. Scale bar: 20 μm. (B) Impaired neuronal maturation in the adult BubR1 ^H/H mice. Sample images of EdU⁺ DCX ⁺NeuN⁻ immature new neurons (red arrows), EdU⁺ DCX ⁺NeuN⁺ intermediate new neurons (white arrows), and EdU⁺ DCX ⁻NeuN⁺ mature new neurons (yellow arrows). Scale bar: 50 μm. All values represent mean ± SEM. *: P < 0.05, **: P < 0.01, ns: no significance, unpaired t‐test. (C) Impaired dendrite morphogenesis of new neurons by BubR1 knockdown. Left: Sample confocal images of GFP ⁺ neurons. Scale bar: 20 μm. Right: Cumulative distribution plots of dendrite analysis of new neurons. Each symbol represents data from a single GFP ⁺ neuron. ***: P < 0.001, Kolmogorov–Smirnov test.