AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

Levenga, Josien; Wong, Helen; Milstead, Ryan; Keller, Bailey N.; LaPlante, Lauren; Hoeffer, Charles A.

doi:10.1101/168336

Cited by 16 publications

(49 citation statements)

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“…The p110 subunit of PI3K converts phosphatidylinositol (3,4)-bisphosphate into phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), leading to activation of the AKT family of serine/threonine kinase AKT1 and AKT3 isoforms in neurons, and AKT2 mostly in astrocytes. 23,24 AKT1 interacts with the pleckstrin homology domain of PIP 3 that enables phosphoinositide- dependent protein kinase 1 to phosphorylate threonine 308/309/305 residues of AKT1. The full activation of AKT1 requires phosphorylation of serine 473/474/472, respectively, by the mammalian target for rapamycin complex 2.…”

Section: Discussionmentioning

confidence: 99%

Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function

Arvanitakis

Wang

Capuano

et al. 2020

Annals of Neurology

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Objective To examine associations of molecular markers of brain insulin signaling with Alzheimer disease (AD) and cognition among older persons with or without diabetes. Methods This clinical–pathologic study was derived from a community‐based cohort study, the Religious Orders Study. We studied 150 individuals (mean age at death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age at death and education). Using enzyme‐linked immunosorbent assay, immunohistochemistry, and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate to death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD, and level of cognition. Results Brain insulin receptor substrate‐1 (IRS1) phosphorylation (pS307IRS1/total IRS1) and serine/threonine‐protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT308AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT308AKT1 was associated with a lower level of global cognitive function (estimate = −0.212, standard error = 0.097; p = 0.031). Interpretation Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function. ANN NEUROL 2020;88:513–525

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Section: Discussionmentioning

confidence: 99%

Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function

Arvanitakis

Wang

Capuano

et al. 2020

Annals of Neurology

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“…39 Furthermore, several studies identified that AKT1 and CREB1 were associated with synaptic plasticity in the hippocampus. 40 Liu et al identified that PIAS1 has an important role in neuronal plasticity, learning and memory function. 41 Also, CDK2AP1 in the yellow module was recently identified as a susceptibility gene for intellectual disability.…”

Section: Discussionmentioning

confidence: 99%

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia

et al. 2019

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BackgroundPrevious studies have inferred a strong genetic component in schizophrenia. However, the genetic variants involved in the susceptibility to schizophrenia remain unclear.AimsTo detect potential gene pathways and networks associated with schizophrenia, and to explore the relationship between common and rare variants in these pathways and abnormal white matter integrity in schizophrenia.MethodThe analysis included 100 first-episode treatment-naïve patients with schizophrenia and 140 healthy controls. A network-based analysis was carried out on the data collected from the Psychiatric Genomics Consortium Phase I (PGC-I). Based on our genome-wide association study and whole-exome sequencing data-sets, we performed a gene-set analysis to detect associations between the combining effects of common and rare genetic variants and abnormal white matter integrity in schizophrenia.ResultsPatients had significantly reduced functional anisotropy in the left and right anterior cingulate cortex, left and right precuneus and extra-nuclear (t = 4.61–5.10, PFDR < 0.01), compared with controls. Generated from co-expression network analysis of the PGC-1 summary statistics of schizophrenia, a subnetwork of 207 genes associated with schizophrenia was identified (P < 0.01), and 176 genes were co-expressed in four gene modules. Functional enrichment analysis for genes in each module revealed that the yellow module was enriched with highly co-expressed, innate immune response genes. Furthermore, rare variants of enriched genes in the yellow module were associated with reduced functional anisotropy in the left anterior cingulate cortex (P = 0.006; Padjusted = 0.024) in patients only.ConclusionsThe pathogenesis of schizophrenia may be substantially influenced by genes involved in the immune system, via both pathway and network.Declaration of interestsNone.

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“…Three different isoforms of AKT exist. Whereas AKT1 and AKT3 are mainly expressed in neurons, AKT2 is predominantly expressed in astrocytes (Levenga et al, 2017). So far, the exact function of AKT in neurons is not clear, but AKT1 has been implicated in late long term potentiation (Levenga et al, 2017) and AKT3 in neuronal growth (Rivière et al, 2012;Adams et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas AKT1 and AKT3 are mainly expressed in neurons, AKT2 is predominantly expressed in astrocytes (Levenga et al, 2017). So far, the exact function of AKT in neurons is not clear, but AKT1 has been implicated in late long term potentiation (Levenga et al, 2017) and AKT3 in neuronal growth (Rivière et al, 2012;Adams et al, 2016). AKT is activated by phosphatidylinositol 3kinase (PI3K) and the PI3K/AKT signaling pathway is known to reduce apoptosis and promote survival and proliferation (Brunet et al, 1999) and thereby counteracts neuronal cell death (Peltier et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Enhancing mitochondrial activity in neurons protects against neurodegeneration in CNS inflammation

Rosenkranz

Shaposhnykov

Träger

et al. 2020

Preprint

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Central nervous system (CNS) inflammation in multiple sclerosis (MS) drives neuro-axonal loss resulting in irreversible disability. While transcripts of mitochondrial genes are strongly suppressed in neurons during CNS inflammation, it is unknown whether this results in mitochondrial dysfunction and whether interventions that increase mitochondrial function can rescue neurodegeneration. Here we show that suppression of mitochondrial gene transcripts in inflamed neurons was predominantly affecting genes of the electron transport chain resulting in impaired mitochondrial complex IV activity. This was associated with posttranslational inactivation of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α). Neuronal overexpression of Pgc-1α led to increased numbers of mitochondria, complex IV activity and elevated maximum respiratory capacity. Moreover, Pgc-1αoverexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Pgc-1α aggravated neurodegeneration during experimental autoimmune encephalomyelitis (EAE), while neuronal overexpression of Pgc-1α ameliorated EAE disease course and preserved neurons. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.

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AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

Cited by 16 publications

References 50 publications

Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function

Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia

Enhancing mitochondrial activity in neurons protects against neurodegeneration in CNS inflammation

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