Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice

Lin, Lanyan; Zhang, Jing; Dai, Xiaoman; Xiao, Naian; Wu, Xilin; Wei, Zhen; Fang, Wenting; Zhu, Yanqiao; Chen, Xiao Chun

doi:10.1186/s13024-016-0107-2

Cited by 26 publications

(28 citation statements)

References 59 publications

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“…3A, E; P , 0.001). In addition, lower levels of ApoE4, as compared to those of ApoE3, have been reported in the brains of young and aged human ApoE4-TR mice (5,29) and probably in aged nondemented APOE4 carriers (30). Indeed, our Western blot analysis revealed that huApoE levels are lower in the hippocampus of ApoE4-TR mice as compared with ApoE3-TR mice (Fig.…”

Section: Resultsmentioning

confidence: 46%

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

et al. 2019

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Aging and apolipoprotein E4 (ApoE4) can increase the risk of cognitive impairment and neurodegenerative disorders, including Alzheimer's disease (AD), and patients with type 2 diabetes mellitus are highly susceptible to cognitive dysfunction. Recent research has indicated that metformin, a prescribed drug for type 2 diabetes, may affect cognitive function; however, findings regarding its efficacy are largely controversial. The current study reported that a 5‐mo metformin administration (300 mg/kg/d) starting at 13 mo old improved the spatial memory of ApoE3‐target replacement (TR) mice, not ApoE4‐TR mice. It found that in aged ApoE3‐TR mice, metformin treatment, at a molecular level, inhibited AMPK activity, increased insulin signaling, and activated mammalian target of rapamycin signaling, resulting in an enhanced expression of postsynaptic proteins; but the response of the neuronal AMPK activity and insulin signaling to metformin was blunt in aged ApoE4‐TR mice. Meanwhile, metformin treatment also increased the phosphorylation of tau in both ApoE3‐TR and ApoE4‐TR mice, implying that metformin may have side effects in human. These findings suggest that metformin can improve the cognitive performance of aged mice in an APOE genotype–dependent manner, which provides empirical insights into the clinical value of metformin for ApoE4‐ and age‐related AD prevention and treatment.—Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., Chen, X. Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner. FASEB J. 33, 7748–7757 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 46%

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

et al. 2019

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“…Chronic stress has been identified as a risk factor for AD and has been utilized in pre-clinical studies to induce AD (Leonard 2017;Lin et al 2016;McEwen 2005;Piirainen et al 2017). Rinwa and Kumar used a 28-day chronic stress paradigm made up of random patterns of mild stressors.…”

Section: Studies Of Aging Induced By Environmental Factorsmentioning

confidence: 99%

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies

Sarker

Franks

2018

GeroScience

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Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov , the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

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“…These alterations may render APOE ε4 carriers more susceptible to AD-related pathology and predict conversion to AD in individuals with mild cognitive impairment (MCI) [ 18 , 19 ]. Studies of APOE ε4-targeted replacement mice proposed a clear link between early-life stress and cognitive impairment in middle-aged mice, but whether these observations are of relevance to humans needs to be confirmed [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Peripheral apoE isoform levels in cognitively normal APOE ε3/ε4 individuals are associated with regional gray matter volume and cerebral glucose metabolism

et al. 2017

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Background: Carriers of the APOE ε4 allele are at increased risk of developing Alzheimer's disease (AD), and have been shown to have reduced cerebral metabolic rate of glucose (CMRgl) in the same brain areas frequently affected in AD. These individuals also exhibit reduced plasma levels of apolipoprotein E (apoE) attributed to a specific decrease in the apoE4 isoform as determined by quantification of individual apoE isoforms in APOE ε4 heterozygotes. Whether low plasma apoE levels are associated with structural and functional brain measurements and cognitive performance remains to be investigated. Methods: Using quantitative mass spectrometry we quantified the plasma levels of total apoE and the individual apoE3 and apoE4 isoforms in 128 cognitively normal APOE ε3/ε4 individuals included in the Arizona APOE cohort. All included individuals had undergone extensive neuropsychological testing and 25 had in addition undergone FDG-PET and MRI to determine CMRgl and regional gray matter volume (GMV). Results: Our results demonstrated higher apoE4 levels in females versus males and an age-dependent increase in the apoE3 isoform levels in females only. Importantly, a higher relative ratio of apoE4 over apoE3 was associated with GMV loss in the right posterior cingulate and with reduced CMRgl bilaterally in the anterior cingulate and in the right hippocampal area. Additional exploratory analysis revealed several negative associations between total plasma apoE, individual apoE isoform levels, GMV and CMRgl predominantly in the frontal, occipital and temporal areas. Finally, our results indicated only weak associations between apoE plasma levels and cognitive performance which further appear to be affected by sex. Conclusions: Our study proposes a sex-dependent and age-dependent variation in plasma apoE isoform levels and concludes that peripheral apoE levels are associated with GMV, CMRgl and possibly cognitive performance in cognitively healthy individuals with a genetic predisposition to AD.

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Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice

Cited by 26 publications

References 59 publications

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies

Peripheral apoE isoform levels in cognitively normal APOE ε3/ε4 individuals are associated with regional gray matter volume and cerebral glucose metabolism

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