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Aging and disease    2019, Vol. 10 Issue (5) : 1058-1074     DOI: 10.14336/AD.2019.0102
Orginal Article |
AMPK Signaling Regulates the Age-Related Decline of Hippocampal Neurogenesis
Brian Z Wang1, Jane J Yang2, Hongxia Zhang1, Charity A Smith1, Kunlin Jin1,*
1Department of Pharmacology & Neuroscience, UNT Health Science Center, TX 76107, USA
2School of Interdisciplinary Studies, University of Texas at Dallas, TX 75080, USA
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Abstract  

The global incidence of age-associated neurological diseases is expected to rise with increasingly greying societies. In the aged brain, there is a dramatic decrease in the number of stem cells, which is a main cause for the decrease in brain function. Intrinsic factors, such as cell metabolism, have been studied but its role in neurogenesis is still unknown. Therefore, this study sought to establish whether AMP-activated protein kinase (AMPK) signaling does indeed regulate hippocampal neurogenesis in the aged brain. We found that i) AMPKα2 was the predominant catalytic subunit in the subgranular and subventricular zones; ii) AMPK activation was at a significantly higher level in the aged vs. young hippocampus; iii) short term (7 days) treatment with selective AMPK signaling inhibitor Compound C (10 mg/kg/day, i.p.) significantly increased the numbers of newborn (BrdU+), Type 2 (MCM2+), and Type 3 (DCX+) neural stem cells, but not Type 1 (GFAP+/Sox2+) cells, in the aged hippocampus. Taken together, our results demonstrate that AMPK signaling plays a critical role in the age-related decline of hippocampal neurogenesis.

Keywords AMPK      metabolism      stem cell      aging      Compound C      AICAR     
Corresponding Authors: Jin Kunlin   
About author:

Present address: Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.

Just Accepted Date: 26 January 2019   Issue Date: 27 September 2019
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Wang Brian Z
Yang Jane J
Zhang Hongxia
Smith Charity A
Jin Kunlin
Cite this article:   
Wang Brian Z,Yang Jane J,Zhang Hongxia, et al. AMPK Signaling Regulates the Age-Related Decline of Hippocampal Neurogenesis[J]. Aging and disease, 2019, 10(5): 1058-1074.
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http://www.aginganddisease.org/EN/10.14336/AD.2019.0102     OR     http://www.aginganddisease.org/EN/Y2019/V10/I5/1058
Figure 1.  Experimental design. Young (2-3 months, orange mouse) and aged (19-20 months, grey mouse) male C57BL/6J mice were randomly divided into the groups outlined in the Materials and Methods section. The infographic here describes the design and timeline for studying the (A) short term and (B) long term effects of forced inhibition and activation of AMPK signaling on hippocampal neurogenesis. (C) Summary of the four stages during adult hippocampal neurogenesis: (1) quiescent radial glia-like (Type 1) cells in the subgranular zone (SGZ) are activated; (2) proliferation of non-radial progenitor (Type 2) cells; (3) generation of neuroblasts (Type 3); (4) maturation of neurons. Also shown are the time course for each stage and expression of stage-specific markers which were utilized for their identification in this study [17, 18]. DCX: doublecortin; GCL: granule cell layer; GFAP: glial fibrillary acidic protein; MCM2: minichromosome maintenance complex component 2; ML: molecular layer; NeuN: neuronal nuclei; SGZ: subgranular zone; Sox2: SRY (sex determining region Y)-box 2.
Figure 2.  Expression patterns of AMPK subunit isoforms in the subgranular zone. (A) The AMPK complex is a heterotrimer made up of α, β, and γ subunits in a 1:1:1 ratio. The β-CTD of the β subunit forms the core of the complex, which binds to the N-terminus of the γ-subunit just before CBS1 and the α-CTD of the α-subunit. Representative images of coronal sections (5 μm) of young and aged mouse brains were immunostained to examine the expression pattern for all 7 AMPK subunit isoforms in the subgranular zone of the dentate gyrus (a 2-3 cell layer demarcated by the red dotted lines) where neurogenesis occurs. The representative images on the left show the expression patterns in the young brain while the right depict the patterns in the aged brain. All isoforms showed a lower expression level in the aged brain and were found in the cytoplasm with the exception of the α2 and β1 isoforms, which were localized to the nucleus. (B) AMPKα1, (C) AMPKα2, (D) AMPKβ1, (E) AMPKβ2, (F) AMPKγ1, (G) AMPKγ2, (H) AMPKγ3. Scale bar: 50 μm, n = 4 per group. AID: autoinhibitory domain; CBM: carbohydrate-binding module; CTD: carboxy-terminal domain; SGZ: subgranular zone.
Figure 3.  Expression patterns of AMPK subunit isoforms in the subventricular zone. Representative images of coronal sections (5 μm) of young and aged mouse brains were immunostained to examine the expression pattern for all 7 AMPK subunit isoforms in the subventricular zone (SVZ) of the lateral ventricles where neurogenesis occurs. The anterior SVZ (aSVZ) shown here has the highest concentration of neural stem cells. The representative figures on the left show the expression patterns in the young brain while the right depict the patterns in the aged brain. All isoforms were localized to the nucleus with the exception of α1, which was found in the cytoplasm. All α and β isoform levels decreased with age with the exception of all three γ isoforms that experienced increased levels with age. (A) AMPKα1, (B) AMPKα2, (C) AMPKβ1, (D) AMPKβ2, (E) AMPKγ1, (F) AMPKγ2, (G) AMPKγ3. Scale bar: 50 μm, n = 4 per group. aSVZ: anterior subventricular zone; CC: corpus callosum; CPu: caudate putamen (striatum).
Figure 4.  AMPK signaling activation is increased in the hippocampus with age. Representative images of coronal sections (5 μm) of young mouse brains were subjected to double- or triple-labeling to demonstrate the colocalization of AMPK signaling activation (pAMPKα) with individual stem cell types (indicated by white arrows) found in the subgranular zone: (A) quiescent Type 1 stem cells (GFAP+/Sox2+), (B) actively proliferating Type 2 progenitor cells (MCM2+), (C) differentiated immature neuroblasts (DCX+). Scale bars in A-C: 50 μm, n = 4 per group. (D) Representative images demonstrating AMPK signaling activation levels in the young and aged dentate gyrus. Scale bar: 100 μm, n = 4 per group. (E) Protein lysates (30 μg) obtained from young and aged hippocampi were resolved on 10% SDS-PAGE gels, transferred onto PVDF membranes and probed with the appropriate primary and secondary antibodies. Representative Western blots show pAMPKα and total AMPKα protein levels. Actin was used as the loading control. (F) Statistical analysis of relative protein levels of pAMPKα in the young and aged hippocampus showing a significant increase in AMPK signaling activation in the aged hippocampus. Data shown as mean ± standard error (SEM), n = 4 per group, *p < 0.05, Student’s t-test. DCX: doublecortin; DG: dentate gyrus; GFAP: glial fibrillary acidic protein; MCM2: minichromosome maintenance complex component 2; Sox2: SRY (sex determining region Y)-box 2.
Figure 5.  AMPK signaling activation is increased in the subventricular zone with age. Representative images of coronal sections (5 μm) of young mouse brains subjected to demonstrate the colocalization of AMPK signaling activation (pAMPKα) with individual stem cell types (indicated by white arrows) found in the SVZ: (A) quiescent Type 1 stem cells (GFAP+/Sox2+), (B) actively proliferating Type 2 progenitor cells (MCM2+), (C) differentiated immature neuroblasts (DCX+). Scale bars in A-C: 50 μm, n = 4 per group. (D) Representative images demonstrating AMPK signaling activation levels in the young and aged SVZ. Scale bar: 100 μm, n = 4 per group. (E) Protein lysates (30 μg) obtained from microdissected young and aged SVZ were resolved on 10% SDS-PAGE gels, transferred onto PVDF membranes and probed with the appropriate primary and secondary antibodies. Representative Western blots show pAMPKα and total AMPKα protein levels. Actin was used as the loading control. (F) Statistical analysis of relative protein levels of pAMPKα in the young and aged SVZ showing an increase in AMPK signaling activation with age. Data shown as mean ± standard error (SEM), n = 4 per group, Student’s t-test. CC: corpus callosum; DCX: doublecortin; GFAP: glial fibrillary acidic protein; LV: lateral ventricle, MCM2: minichromosome maintenance complex component 2; Sox2: SRY (sex determining region Y)-box 2; SVZ: subventricular zone.
Figure 6.  Pharmacological inhibition of AMPK signaling with Compound C increases hippocampal neurogenesis. Young and aged mice were subjected to intraperitoneal administration of vehicle (0.9% saline) or specific AMPK inhibitor (Compound C, 10 mg/kg/day) for 7 and 28 days. (A) Protein lysates (30 μg) from the young vehicle and inhibitor groups were resolved on 10% SDS-PAGE gels, transferred onto PVDF membranes and probed with the appropriate primary and secondary antibodies. Representative Western blots show pAMPKα and total AMPKα protein levels. Actin was used as the loading control. Statistical analysis of relative protein levels of pAMPKα in the young hippocampus indicating that Compound C mediated neurogenesis was AMPK-dependent. Data shown as mean ± standard error (SEM), n = 4 per group, *p < 0.05, **p < 0.01, Student’s t-test. Representative immunostaining for (B) newborn BrdU+ neural stem cells (NSCs), (D) GFAP+/Sox2+ Type 1 NSCs, (F) MCM2+ Type 2 NSCs, and (H) DCX+ Type 3 NSCs in the DG and SGZ of young mice. Scale bars in left panels of (B), (F), (H): 500 µm, Scale bars in right panels of (B), (F), (H): 50 µm, Scale bars in (D): top panel, 200 µm; bottom panel, 50 µm. Quantification of (C) newborn, (E) Type 1, (G) Type 2, and (I) Type 3 NSCs in the young and aged SGZ after short- and long-term treatment with Compound C. Data shown as mean ± standard error (SEM), n = 5-6 mice/group/time point, 4-6 sections per animal, *p < 0.05, **p < 0.01, Two-way ANOVA (between-groups factors: treatment, treatment duration) followed by Fisher’s LSD post hoc test. DCX: doublecortin; DG: dentate gyrus; GFAP: glial fibrillary acidic protein; MCM2: minichromosome maintenance complex component 2; SGZ: subgranular zone; Sox2: SRY (sex determining region Y)-box 2.
Figure 7.  Pharmacological activation of AMPK signaling with AICAR does not impact hippocampal neurogenesis in the male mouse. Young and aged mice were subjected to intraperitoneal administration of vehicle (0.9% saline) or specific AMPK activator (AICAR, 500 mg/kg/day) for 7 and 28 days. (A) Protein lysates (30 μg) from the young vehicle and activator groups were resolved on 10% SDS-PAGE gels, transferred onto PVDF membranes and probed with the appropriate primary and secondary antibodies. Representative Western blots show pAMPKα and total AMPKα protein levels. Actin was used as the loading control. (B) Statistical analysis of relative protein levels of pAMPKα in the young hippocampus revealed that AICAR failed to activate AMPK signaling. Data shown as mean ± standard error (SEM), n = 4 per group, Student’s t-test. Quantification of (C) newborn, (D) Type 1, (E) Type 2, and (F) Type 3 NSCs in the young and aged SGZ after short- and long-term treatment with AICAR. Data shown as mean ± standard error (SEM), n = 5-6 mice/group/time point, 4-6 sections per animal, Two-way ANOVA (between-groups factors: treatment, treatment duration) was performed but we found no significant interactions. (G-H) To rule out the possibility of obtaining a bad lot of the drug, we administered AICAR (4 mM) centrally for 3 days using a minipump with flow rate of 1 μL/hr and found that AICAR could indeed activate AMPK signaling, raising the possibility that AICAR was not able to cross the blood-brain-barrier in the male mouse. Data shown as mean ± standard error (SEM), n = 3 per group, ***p < 0.001, Student’s t-test. DCX: doublecortin; GFAP: glial fibrillary acidic protein; ICV: intracerebroventricular; IP: intraperitoneal; MCM2: minichromosome maintenance complex component 2; Sox2: SRY (sex determining region Y)-box 2.
Figure 8.  Long-term administration of AMPK inhibitor and activator does not alter the mouse’s vital signs. Young and aged mice were subjected to intraperitoneal administration of vehicle (0.9% saline), inhibitor (Compound C, 10 mg/kg/day), or activator (AICAR, 500 mg/kg/day) for 28 days. Measurements for (A) body weight and (B) spontaneous locomotor activity were taken every week at 9 am, n = 4 per group, Two-way ANOVA (between-groups factors: treatment, treatment duration) was performed but we found no significant interactions.
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