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Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

Ali AA, Schwarz-Herzke B, Stahr A, Prozorovski T, Aktas O, von Gall C - Aging (Albany NY) (2015)

Bottom Line: Hippocampal neurogenesis undergoes dramatic age-related changes.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.In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Institute for Anatomy II, Medical Faculty, Heinrich Heine University, D-40225, Düsseldorf, Germany.

ABSTRACT
Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (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 70 kDa 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.

No MeSH data available.


Related in: MedlinePlus

Survival of NPCs was enhanced in Bmal1‐/‐ miceSurviving BrdU+ cells were analyzed 28 days after the final BrdU administration. (A) Representative photomicrographs of BrdU+ cells. (B) Quantification of BrdU+ cells in DG. The number of BrdU+ cells was significantly smaller in Bmal1‐/‐ as compared to Bmal1+/+. (C) Linear regression of BrdU+ cells one day and 28 days after final BrdU‐injection showed significantly steeper slope in Bmal1+/+ as compared to Bmal1‐/‐. (D) Representative photomicrographs showing caspase3+ cells. (E) Quantification of caspase3+ cells in DG. The number of caspase3+ cells was significantly lower in Bmal1‐/‐ as compared to Bmal1+/+. Values are given as mean + SEM, *: P <0.05, scale bar = 50 μm.
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Figure 4: Survival of NPCs was enhanced in Bmal1‐/‐ miceSurviving BrdU+ cells were analyzed 28 days after the final BrdU administration. (A) Representative photomicrographs of BrdU+ cells. (B) Quantification of BrdU+ cells in DG. The number of BrdU+ cells was significantly smaller in Bmal1‐/‐ as compared to Bmal1+/+. (C) Linear regression of BrdU+ cells one day and 28 days after final BrdU‐injection showed significantly steeper slope in Bmal1+/+ as compared to Bmal1‐/‐. (D) Representative photomicrographs showing caspase3+ cells. (E) Quantification of caspase3+ cells in DG. The number of caspase3+ cells was significantly lower in Bmal1‐/‐ as compared to Bmal1+/+. Values are given as mean + SEM, *: P <0.05, scale bar = 50 μm.

Mentions: Survival of NPCs in DG was analyzed 28 days after the last BrdU administration. The number of BrdU positive cells was significantly reduced by about 28.2% in Bmal1−/− mice (647±83.9) as compared to Bmal1+/+ mice (901.2±52.97) (P=0.03) (Fig. 4A, B), consistently with a reduced total number of NPCs in adult Bmal1−/− mice. Linear regression revealed a steeper slope in Bmal1+/+ mice as compared to Bmal1−/− mice (P=0.028) (Fig. 4C), indicating a higher survival rate in Bmal1−/− mice. Consistently, the number of caspase3+ cells/mm2 in DG was significantly decreased in Bmal1−/− (136.5±5.1) as compared to Bmal1+/+ mice (369.3 ± 33.60) (P=0.028) (Fig. 4D, E), indicating decreased cell death in DG of Bmal1−/− mice.


Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

Ali AA, Schwarz-Herzke B, Stahr A, Prozorovski T, Aktas O, von Gall C - Aging (Albany NY) (2015)

Survival of NPCs was enhanced in Bmal1‐/‐ miceSurviving BrdU+ cells were analyzed 28 days after the final BrdU administration. (A) Representative photomicrographs of BrdU+ cells. (B) Quantification of BrdU+ cells in DG. The number of BrdU+ cells was significantly smaller in Bmal1‐/‐ as compared to Bmal1+/+. (C) Linear regression of BrdU+ cells one day and 28 days after final BrdU‐injection showed significantly steeper slope in Bmal1+/+ as compared to Bmal1‐/‐. (D) Representative photomicrographs showing caspase3+ cells. (E) Quantification of caspase3+ cells in DG. The number of caspase3+ cells was significantly lower in Bmal1‐/‐ as compared to Bmal1+/+. Values are given as mean + SEM, *: P <0.05, scale bar = 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4505169&req=5

Figure 4: Survival of NPCs was enhanced in Bmal1‐/‐ miceSurviving BrdU+ cells were analyzed 28 days after the final BrdU administration. (A) Representative photomicrographs of BrdU+ cells. (B) Quantification of BrdU+ cells in DG. The number of BrdU+ cells was significantly smaller in Bmal1‐/‐ as compared to Bmal1+/+. (C) Linear regression of BrdU+ cells one day and 28 days after final BrdU‐injection showed significantly steeper slope in Bmal1+/+ as compared to Bmal1‐/‐. (D) Representative photomicrographs showing caspase3+ cells. (E) Quantification of caspase3+ cells in DG. The number of caspase3+ cells was significantly lower in Bmal1‐/‐ as compared to Bmal1+/+. Values are given as mean + SEM, *: P <0.05, scale bar = 50 μm.
Mentions: Survival of NPCs in DG was analyzed 28 days after the last BrdU administration. The number of BrdU positive cells was significantly reduced by about 28.2% in Bmal1−/− mice (647±83.9) as compared to Bmal1+/+ mice (901.2±52.97) (P=0.03) (Fig. 4A, B), consistently with a reduced total number of NPCs in adult Bmal1−/− mice. Linear regression revealed a steeper slope in Bmal1+/+ mice as compared to Bmal1−/− mice (P=0.028) (Fig. 4C), indicating a higher survival rate in Bmal1−/− mice. Consistently, the number of caspase3+ cells/mm2 in DG was significantly decreased in Bmal1−/− (136.5±5.1) as compared to Bmal1+/+ mice (369.3 ± 33.60) (P=0.028) (Fig. 4D, E), indicating decreased cell death in DG of Bmal1−/− mice.

Bottom Line: Hippocampal neurogenesis undergoes dramatic age-related changes.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.In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Institute for Anatomy II, Medical Faculty, Heinrich Heine University, D-40225, Düsseldorf, Germany.

ABSTRACT
Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (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 70 kDa 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.

No MeSH data available.


Related in: MedlinePlus