Regional hippocampal differences in AKT survival signaling across the lifespan: implications for CA1 vulnerability with aging

Jackson, T. L.; Rani, Asha; Kumar, Ashok; Foster, Thomas C.

doi:10.1038/cdd.2008.171

Cited by 51 publications

(54 citation statements)

References 42 publications

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“…17 Furthermore, it has been recently described that regional variations in PHLPP1 protein levels in rat hippocampus could account for the differences in pAkt (Ser473) levels. 22 In agreement, in the striatum of all HD models analyzed, we observed increased pAkt (Ser473) levels in the same conditions where PHLPP1 protein levels were reduced. Furthermore, we also detected increased pAkt (Thr308) levels in R6/1 mouse striatum at 12 and 30 weeks of age.…”

Section: Discussionsupporting

confidence: 72%

“…In line with this, the phosphorylation status of Akt has been shown to determine neuronal survival or death after cerebral ischemia 9,10 and to participate in the different vulnerability of CA1 and CA3 hippocampal neurons to cellular stress. 22 In summary, in this work we show that one of the cellular responses to full-length or N-terminal exon-1 mhtt expression is the reduction of PHLPP1 protein levels, which is initiated at early stages and persists during the course of the disease. In addition, only striatal cells respond to the stress caused by mhtt activating the PI3K/Akt pathway.…”

Section: Actinmentioning

confidence: 99%

“…20 Recently, it has been shown that PHLPP1 participates in the regulation of MAPK signaling required for some forms of hippocampus-dependent memory, 21 and that changes in total PHLPP1 protein levels are important in regulating the degree of Akt phosphorylation at Ser473 in the hippocampus. 22 Because the presence of mhtt can result in alteration of gene expression, 23 in the present work we sought to determine whether mhtt could induce changes in PHLPP1 protein levels contributing to maintain high levels of pAkt (Ser473) in transgenic mouse models and in the brain of HD patients.…”

mentioning

confidence: 99%

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PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

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Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh Q111/Q111 mouse striatum and STHdh Q111/Q111 cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF þ /À, R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing.

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Section: Discussionsupporting

confidence: 72%

Section: Actinmentioning

confidence: 99%

mentioning

confidence: 99%

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PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

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“…Regions in the Ammon's horn (CA1-CA4) can be distinguished according to their morphologies, their connectivity, and their electrophysiological properties reflecting basic molecular differences as has been demonstrated by proteomic or genomic analysis in adult rat hippocampus. 54 -57 Differential susceptibility to insults, such as seizures or HI, between CA1 and CA3 might result from their distinct patterns of protein/gene expression, and globally, CA1 appeared to present a basal molecular profile that makes it more vulnerable to apoptosis, at least in adult rats, 54,57 but less is known about the neonatal hippocampus.…”

Section: In the Hippocampus The Autophagic Phenotype Of Cell Death Omentioning

confidence: 99%

Enhancement of Autophagic Flux after Neonatal Cerebral Hypoxia-Ischemia and Its Region-Specific Relationship to Apoptotic Mechanisms

Ginet

Puyal

Clarke

et al. 2009

The American Journal of Pathology

141

152

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The multiplicity of cell death mechanisms induced by neonatal hypoxia-ischemia makes neuroprotective treatment against neonatal asphyxia more difficult to achieve. Whereas the roles of apoptosis and necrosis in such conditions have been studied intensively, the implication of autophagic cell death has only recently been considered. Here, we used the most clinically relevant rodent model of perinatal asphyxia to investigate the involvement of autophagy in hypoxic-ischemic brain injury. Seven-day-old rats underwent permanent ligation of the right common carotid artery, followed by 2 hours of hypoxia. This condition not only increased autophagosomal abundance (increase in microtubule-associated protein 1 light chain 3-11 level and punctuate labeling) but also lysosomal activities (cathepsin D, acid phosphatase, and ␤-Nacetylhexosaminidase) in cortical and hippocampal CA3-damaged neurons at 6 and 24 hours, demonstrating an increase in the autophagic flux. In the cortex, this enhanced autophagy may be related to apoptosis since some neurons presenting a high level of autophagy also expressed apoptotic features, including cleaved caspase-3. On the other hand, enhanced autophagy in CA3 was associated with a more purely autophagic cell death phenotype. In striking contrast to CA3 neurons, those in CA1 presented only a minimal increase in autophagy but strong apoptotic characteristics. These results suggest a role of enhanced autophagy in delayed neuronal death after severe hypoxia-ischemia that is differentially linked to apoptosis according to the cerebral region. (Am J Pathol 2009,

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“…Here we investigate if several PHLPP inhibitors (NSC117079 and NSC45586) selectively activate AKT in primary rat cortical neurons and astrocytes. Furthermore, because PHLPP1 is abundant in the ischemia vulnerable CA1 hippocampal subregion and it inhibits AKT activation in primary hippocampal neurons, we explored if key brain phosphatases (including PHLPP1 and PHLPP2) increased in the rat hippocampus after CA (Jackson et al, 2009(Jackson et al, , 2010.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of Pleckstrin Homology Domain Leucine-Rich Repeat Protein Phosphatase Is Neuroprotective: Differential Effects on Astrocytes

Jackson

Verrier

Drábek

et al. 2013

J Pharmacol Exp Ther

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Pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) inhibits protein kinase B (AKT) survival signaling in neurons. Small molecule pan-PHLPP inhibitors (selective for PHLPP1 and PHLPP2) may offer a translatable method to induce AKT neuroprotection. We tested several recently discovered PHLPP inhibitors (NSC117079 and NSC45586; benzoic acid,-2-hydroxy-,sodium salt.) in rat cortical neurons and astrocytes and compared the biochemical response of these agents with short hairpin RNA (shRNA)-mediated PHLPP1 knockdown (KD). In neurons, both PHLPP1 KD and experimental PHLPP inhibitors activated AKT and ameliorated staurosporine (STS)-induced cell death. Unexpectedly, in astrocytes, both inhibitors blocked AKT activation, and NSC117079 reduced viability. Only PHLPP2 KD mimicked PHLPP inhibitors on astrocyte biochemistry. This suggests that these inhibitors could have possible detrimental effects on astrocytes by blocking novel PHLPP2-mediated prosurvival signaling mechanisms. Finally, because PHLPP1 levels are reportedly high in the hippocampus (a region prone to ischemic death), we characterized hippocampal changes in PHLPP and several AKT targeting prodeath phosphatases after cardiac arrest (CA)-induced brain injury. PHLPP1 levels increased in rat brains subjected to CA. None of the other AKT inhibitory phosphatases increased after global ischemia (i.e., PHLPP2, PTEN, PP2A, and PP1). Selective PHLPP1 inhibition (such as by shRNA KD) activates AKT survival signaling in neurons and astrocytes. Nonspecific PHLPP inhibition (by NSC117079 and NSC45586) only activates AKT in neurons. Taken together, these results suggest that selective PHLPP1 inhibitors should be developed and may yield optimal strategies to protect injured hippocampal neurons and astrocytesnamely from global brain ischemia.

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Regional hippocampal differences in AKT survival signaling across the lifespan: implications for CA1 vulnerability with aging

Cited by 51 publications

References 42 publications

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Enhancement of Autophagic Flux after Neonatal Cerebral Hypoxia-Ischemia and Its Region-Specific Relationship to Apoptotic Mechanisms

Pharmacological Inhibition of Pleckstrin Homology Domain Leucine-Rich Repeat Protein Phosphatase Is Neuroprotective: Differential Effects on Astrocytes

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