Genome-wide RNA sequencing analysis reveals that IGF-2 attenuates memory decline, oxidative stress and amyloid plaques in an Alzheimer’s disease mouse model (AD) by activating the PI3K/AKT/CREB signaling pathway

Xia, Lei; Zhu, Xiangyu; Zhao, Ying; Yang, Guang; Zuo, Xiaohua; Xie, Peng; Chen, Chun; Han, Qian

doi:10.1017/s1041610219000383

Cited by 19 publications

(35 citation statements)

References 33 publications

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“…Decreased levels of PI3K subunits, as well as blunted AKT kinase phosphorylation, have been observed in the brain of AD patients [64]. Insulin-like growth factor-2 (IGF-2) was reported to attenuates memory decline and amyloid plaques plaque formation in AD mouse model by activating the PI3K/AKT/CREB signaling pathway [65]., and insulin has been observed to promote neuron growth and synapse formation through the PI3K signal pathway [64,66]. Therefore, we speculate that SV2A may play a role in promoting insulin growth factor secretion.…”

Section: Discussionmentioning

confidence: 99%

The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

Kong

Huang

Liu

et al. 2020

Preprint

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Background:Alzheimer’s Disease(AD), a serious neurodegenerative disease,is pathologicallycharacterized by synaptic loss and dysfunction.Synaptic vesicle protein 2A (SV2A) is an indispensable vesicular protein specifically expressed in synapses and can be used as a biomarker for synaptic density. Nevertheless, the involvement of SV2A in the pathogenesis and development of ADand its relation to other hallmarks of AD pathology, such as amyloid precursor protein (APP), β-amyloid (Aβ), and tau protein are not fully understood.Methods:We first examined and compared the mRNA levels of SV2A in the hippocampus of AD patients and non-AD subject in the Allen Brain database,thenwe constructed SV2A knockout mouse model.Using PET imagingwe compared the expression of Aβ in SV2A knockout mice and WT mice, analyze the relationship between SV2A and AD related proteins by quantitative real-time polymerase chain reaction (PCR), western blotting and ELISA.Results:Our results showed thatthe expression of SV2A was downregulated in the hippocampus of AD patients.In addition,SV2A colocalized with APPandwas downregulated at Aβ deposition. Moreover, we used APPswe293T cells lines to either silence or overexpress SV2A and found that SV2A deficiency leads to a simultaneous increase in Aβand Tau hyperphosphorylation,whileSV2A overexpression was associated with down-regulation of BACE1 and APOE. In addition, evidence gained in the study points PI3K signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. Conclusions:Our research demonstrated that SV2A is an important regulator of AD, close interplay between SV2A and AD related proteins demonstrated in our studyprovide novel diagnostic and therapeutic opportunities of AD. This study provides guidelines and information regarding the mechanism of SV2A influence in the regulation of AD and possible future research of neurological diseases.

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Section: Discussionmentioning

confidence: 99%

The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

Kong

Huang

Liu

et al. 2020

Preprint

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“…In an in vitro study of the mHypoA‐2 /12β hypothalamic cell line, insulin leads to activation of the CRH promoter primarily through activation of the cyclic adenosine monophosphate/AMP protein kinase A (cAMP/ PKA) pathway and the PI3K/ AKT pathway, 59,60 for CRH promoter contains cAMP response element‐binding protein (CREB) binding site that binds to the major transcription factors to stimulate transcription of the CRH gene 61,62 . After the use of PI3K inhibitors, insulin stimulation is reversed 60 (Figure 2).…”

Section: Effect Of Insulin On Depressionmentioning

confidence: 99%

Potential role of insulin on the pathogenesis of depression

et al. 2020

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| INTRODUC TI ONDiabetes is a metabolic disease characterized by hyperglycaemia due to the defect of insulin secretion or impaired insulin biological effect. A survey has shown that about 30% of people with diabetes also suffer from depression and 10% have severe depression, which suggests a close relationship between the two diseases. 1,2 The mechanism of depression as a complication of diabetes is not completely clear, but studies have found that insulin deficiency or insulin resistance is the symptom that can also be observed in major depression disorder. [3][4][5] Insulin is the only hormone in the human body that reduces the blood glucose level and promotes the synthesis of glycogen, fat and protein. Several studies found that insulin had the ability to affect the nervous system. 6-8 Insulin receptors were distributed in other parts of the brain, except for the parts related to food intake and energy. 9-11 Experiments have gradually revealed other functions of insulin in the brain, for instance promoting memory, protecting neurons, regulating synaptic plasticity and maintaining HPA axis homeostasis. [12][13][14] These effects of insulin may provide a background for its relationship with depression. 15,16 In this case, although there is no direct evidence supporting the link between insulin and treatment for depression, more and more researches support this hypothesis. Here, we review the relationship between insulin signalling and neurophysiological homeostasis, neurotrophic metabolism, cellular pathways and some survey statistics.The exploration of these links and the validation of more relevant mechanisms will develop a new impact on the way of the diagnosis and treatment of depression. | IN SULIN AND DEPRE SS I ONAs early as 1980s, many evidences proved that insulin influenced depression and functional insulin receptors were widely present in the brain. [17][18][19] Data from clinical and epidemiological studies demonstrate a two-way link between emotion and metabolic dysfunction. In young depression patients, insulin sensitivity is significantly decreased. 20,21 Compared with "low insulin" (1.5 mU/kg × min), "high insulin" (15 mU/kg × min) induces a more pronounced of the ability to remember word lists in human being. 22 Intranasal delivery of insulin in awake mice can transmit regulatory and metabolic AbstractThe regulation of insulin on depression and depression-like behaviour has been widely reported. Insulin and activation of its receptor can promote learning and memory, affect the hypothalamic-pituitary-adrenal axis (HPA) balance, regulate the secretion of neurotrophic factors and neurotransmitters, interact with gastrointestinal microbiome, exert neuroprotective effects and have an impact on depression. However, the role of insulin on depression remains largely unclear. Therefore, in this review, we summarized the potential role of insulin on depression. It may provide new insight for clarifying role of insulin on the pathogenesis of depression.

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“…In an investigation that both replicates and extends on the work of Pascual-Lucas et al (2014), Xia et al (2019) utilized the Tg2576 AD mouse model to examine the impact of IGF-2 on memory consolidation, using a Morris Water Maze. The Tg2576 mouse is among the most widely used rodent models of AD.…”

mentioning

confidence: 90%

“…Over 5 million older adults are currently diagnosed with AD, and this number is expected to more than double by 2050. As Xia et al (2019) remind us, the two pathological hallmarks of AD are amyloid plaques, which are enriched with extracellular amyloid beta (Aβ), and intracellular neurofibrillary tangles, which are composed of hyperphosphorylated tau proteins. These pathological features of AD impair neuronal and synaptic function, resulting in an associated decline in cognitive abilities (Allegri et al, 2019;Mirandez et al, 2017).…”

mentioning

confidence: 99%

“…Thus, the search for novel therapeutics continues. What is clear from the work of Xia et al (2019) presented in the current issue of International Psychogeriatrics is that sometimes we have to revisit our past to find the best approaches in the present. In this issue, Xia et al (2019) report on an investigation of the impact of insulin growth factor (IGF)-2 on hippocampal cells and memory function, in a mouse model of AD.…”

mentioning

confidence: 99%

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Rediscovering an old friend: a role for insulin growth factor-2 in reducing neurodegeneration, decreasing amyloid beta, and improving memory

O’Hara

Hallmayer

2019

Int. Psychogeriatr.

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Genome-wide RNA sequencing analysis reveals that IGF-2 attenuates memory decline, oxidative stress and amyloid plaques in an Alzheimer’s disease mouse model (AD) by activating the PI3K/AKT/CREB signaling pathway

Cited by 19 publications

References 33 publications

The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

Potential role of insulin on the pathogenesis of depression

Rediscovering an old friend: a role for insulin growth factor-2 in reducing neurodegeneration, decreasing amyloid beta, and improving memory

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