APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice

Pontifex, Matthew G.; Martinsen, Anneloes; Saleh, Rasha Noureldin M.; Harden, Glenn; Tejera, Noemı́; Müller, Michael; Fox, Chris; Vauzour, David; Minihane, Anne‐Marie

doi:10.1096/fj.202002621rr

Cited by 25 publications

(36 citation statements)

References 115 publications

(199 reference statements)

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“…To assess the impact of FMT upon cognition and behavior, Y-maze spontaneous alternation test and novel object recognition (NOR) were performed as previously described [ 91 ]. Aged mice were tested pre- and post-FMT with young donor fecal microbiota ( n = 10) and compared with aged control mice receiving aged donor microbiota ( n = 10), and with young baseline mice ( n = 11).…”

Section: Methodsmentioning

confidence: 99%

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

et al. 2022

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Background Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Methods Using fecal microbiota transplantation, we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing. Results We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota. Conclusions These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut–brain and gut–retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life. Graphical abstract

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Section: Methodsmentioning

confidence: 99%

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

et al. 2022

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“…DHA is known to increase the level of brain-derived neurotrophic factor and consequently activates protein kinase B (AkT) and extracellular signal-regulated kinase signalling pathways leading to improved synaptic plasticity (69) . Reduced recognition memory was evident in menopausal APOE4 mice models fed with a high-fat diet (10) . This memory deficit was associated with a 13 % reduction in cortical DHA, reduced brain-derived neurotrophic factor expression and compromised Akt, mammalian target of rapamycin and extracellular signal-regulated kinase signalling pathways, highlighting the mechanistic role of DHA, interacting with menopause and APOE4 , in cognitive decline via modulation of synaptic plasticity-related pathways (10) .…”

Section: The Role Of Dha In the Brainmentioning

confidence: 99%

“…This sex difference in dementia-associated death rates is reflective of the fact that two-thirds of dementia patients are females (2) , the physiological and molecular basis of which is only partially elucidated (5)(6)(7) . Accelerated neuropathology and cognitive decline, evident during the menopausal transition in females, and the higher penetrance of the at-risk APOE4 allele in female carriers are likely to be major contributing factors (8)(9)(10)(11) .…”

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confidence: 99%

Fish, n-3 fatty acids, cognition and dementia risk: not just a fishy tale

Saleh

Minihane

2021

Proc. Nutr. Soc.

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With growing and ageing populations, the incidence of dementia is expected to triple globally by 2050. In the absence of effective drugs to treat or reverse the syndrome, dietary approaches which prevent or delay disease onset have considerable population health potential. Prospective epidemiological studies and mechanistic insight from experimental models strongly support a positive effect of a high fish and long chain n-3 fatty acid (EPA and DHA) intake on a range of cognitive outcomes and dementia risk, with effect sizes equivalent to several years of ageing between the highest and lowest consumers. As reviewed here, an effect of EPA and DHA on neuroinflammation and oxylipin production is likely to in part mediate the neurophysiological benefits. However, randomised controlled trials (RCTs) with EPA and DHA supplementation have produced mixed findings. Insight into the likely modulators of response to intervention and factors which should be considered for future RCTs are given. Furthermore, the impact of APOE genotype on disease risk and response to EPA and DHA supplementation is summarised. The prevalence of dementia is several-fold higher in APOE4 females (about 13% Caucasian populations) relative to the general population, who are emerging as a subgroup who may particularly benefit from DHA intervention, prior to the development of significant pathology.

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“…Behavioural tests were performed as previously described [ 48 , 49 ] on mice aged to 14 months old. Objects and arenas were cleaned with 70% ( v/v ) ethanol in between each trial.…”

Section: Methodsmentioning

confidence: 99%

The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer’s Disease

Swingler

Niu

Pontifex

et al. 2022

IJMS

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The complete molecular mechanisms underlying the pathophysiology of Alzheimer’s disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpression of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression decreases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice (p = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. BACE1 and TAU were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of APP, BACE1 and TAU in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance.

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APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 25 publications

References 115 publications

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

Fish, n-3 fatty acids, cognition and dementia risk: not just a fishy tale

The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer’s Disease

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