Research Paper Volume 7, Issue 6 pp 435—449
Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice
- 1 Institute for Anatomy II, Medical Faculty, Heinrich Heine University, D‐40225, Düsseldorf, Germany
- 2 Department of Neurology, Medical Faculty, Heinrich Heine University, D‐40225 Düsseldorf, Germany
Received: March 12, 2015 Accepted: June 20, 2015 Published: June 27, 2015
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Copyright: © 2022 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Hippocampal neurogenesis undergoes dramatic age‐related changes. Mice with targeted deletion of the clock gene Bmal1 (Bmal1‐/‐) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1‐/‐ mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1‐/‐ mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70kDa and expression of the cell cycle inhibitor p21 Waf1/CIP1 were increased in adult Bmal1‐/‐ mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age‐dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.
SGZ: subgranular zone; DG: dentate gyrus; SVZ: subventricular zone; BMAL1: brain and muscle Arnt‐like protein1; CLOCK: circadian locomotor output cycles; Bmal1‐/‐: Bmal1‐deficient mice; Bmal1+/+: wildtype littermates; NPCs: neuronal progenitor/precursor cells; Sirt1: Sirtuine 1; PMP70: Peroxisomal membrane protein at 70kDa; BrdU: bromodeoxyuridine; DAB: diaminobezidine; GCL: granular cell layer; NAD: nicotinamide adenine dinucleotide; HDAC: histone deacetylase; prdx 1: peroxiredoxin 1; mt: metallothionein; FGF: fibroblast growth factor; BDNF: brain derived neurotrophic factor; ROS: reactive oxygen species.