Glucose Metabolism, Neural Cell Senescence and Alzheimer’s Disease

Wang, Qianqian; Duan, Linyan; Li, Xingfan; Wang, Yifu; Guo, Wenna; Guan, Fangxia; Ma, Shanshan

doi:10.3390/ijms23084351

Cited by 49 publications

(30 citation statements)

References 171 publications

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“…Indeed, astrocytes also showed features of the SASP such as interleukin signaling and G-CSF ( Coppé et al, 2010 ). Additionally, metabolism was affected, appearing as altered metal iron homeostasis, a feature of Alzheimer’s disease ( Isaev et al, 2020 ) and increased glucose metabolism and insulin-glucose signaling, a feature of senescence ( Wang et al, 2022 ). Indeed, the latter is closely linked to senescence-associated autophagy ( Rajendran et al, 2019 ) an effect seen in this cell type.…”

Section: Resultsmentioning

confidence: 99%

Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner

et al. 2022

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Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms driving this remain unclear, and currently there are no effective therapies for mTBI. In this study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice have prolonged righting reflexes and astrogliosis, with neurological impairment in the Morris water maze (MWM) and the light dark test. Cortical and hippocampal tissue analysis revealed DNA damage in the form of double-strand breaks, oxidative damage, and R-loops, markers of cellular senescence including p16 and p21, and signaling mediated by the cGAS-STING pathway. This study identified novel sex differences after rmTBI in mice. Although these markers were all increased by rmTBI in both sexes, females had higher levels of DNA damage, lower levels of the senescence protein p16, and lower levels of cGAS-STING signaling proteins compared to their male counterparts. Single-cell RNA sequencing of the male rmTBI mouse brain revealed activation of the DNA damage response, evidence of cellular senescence, and pro-inflammatory markers reminiscent of the senescence-associated secretory phenotype (SASP) in neurons and glial cells. Cell-type specific changes were also present with evidence of brain immune activation, neurotransmission alterations in both excitatory and inhibitory neurons, and vascular dysfunction. Treatment of injured mice with the senolytic drug ABT263 significantly reduced markers of senescence only in males, but was not therapeutic in females. The reduction of senescence by ABT263 in male mice was accompanied by significantly improved performance in the MWM. This study provides compelling evidence that senescence contributes to brain dysfunction after rmTBI, but may do so in a sex-dependent manner.

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Section: Resultsmentioning

confidence: 99%

Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner

et al. 2022

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“…In addition to the TPI abnormalities, the lactate dehydrogenase (LDH) activity level increases in aged brains. LDH reduces pyruvate concentration by catalyzing pyruvate to lactate in neurons [ 22 , 23 , 24 ]. A reduction in pyruvate levels alters the antioxidant defense mechanism and oxidative phosphorylation (OXPHOS) in mitochondria [ 25 , 26 ], triggering oxidative stress and a misfolding protein response.…”

Section: Cerebral Glucose Metabolismmentioning

confidence: 99%

Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions

Kim

Bishayee

2022

IJMS

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Alzheimer’s disease (AD) is the most common age-related dementia. The alteration in metabolic characteristics determines the prognosis. Patients at risk show reduced glucose uptake in the brain. Additionally, type 2 diabetes mellitus increases the risk of AD with increasing age. Therefore, changes in glucose uptake in the cerebral cortex may predict the histopathological diagnosis of AD. The shifts in glucose uptake and metabolism, insulin resistance, oxidative stress, and abnormal autophagy advance the pathogenesis of AD syndrome. Here, we summarize the role of altered glucose metabolism in type 2 diabetes for AD prognosis. Additionally, we discuss diagnosis and potential pharmacological interventions for glucose metabolism defects in AD to encourage the development of novel therapeutic methods.

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“…There has been exhaustive research on JNK and the MAP kinases in AD (comprehensively reviewed by (95)(96)(97) and inhibitors have been designed to target these kinases (98). However, aside from the reported associations of this kinase family to canonical AD pathology, JNK has also been implicated to confer insulin resistance (99), as it phosphorylates the insulin receptor substrate 1 (100) and may impair downstream signaling through the P13K/Akt pathway (101). Intron-4 deletion astrocytes (A), the female PSN1 Intron-4 deletion neurons (B), the male V717I astrocytes (C), the male V717I neurons.…”

Section: The Underrepresented Kinasesmentioning

confidence: 99%

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Henkel

Joyce

Shedroff

et al. 2022

Preprint

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Neurons and astrocytes derived from Alzheimers Disease (AD) patient induced pluripotent stem cells are an evolving technology used to study the pathogenesis and etiology of AD. As the utility of mouse models of AD are increasingly coming into questions, using iPSC technology may offer an opportunity to study this disease with human substrates. Herein, we using a hypothesis generating platform, the PamGene12 Kinome Array, to identify core protein kinases in neurons and astrocytes derived from familial AD patient iPSCs. We identified five core protein kinases in these cells and examined the pathways in which they are enriched. Importantly, we complement our findings using an in-silico approach with postmortem AD brain datasets. While these protein kinases have been conceptualized in the context of traditional AD pathology, they have not been explored in the context of aberrant signaling in the pathophysiology of the disease.

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Glucose Metabolism, Neural Cell Senescence and Alzheimer’s Disease

Cited by 49 publications

References 171 publications

Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner

Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner

Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

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