Assessing Sex-Specific Circadian, Metabolic, and Cognitive Phenotypes in the AβPP/PS1 and APPNL-F/NL-F Models of Alzheimer’s Disease

Britz, Jesse; Ojo, Emmanuel; Dhukhwa, Asmita; Saito, Takashi; Saido, Takaomi C.; Hascup, Erin R.; Hascup, Kevin N.; Tischkau, Shelley A.

doi:10.3233/jad-210629

Cited by 9 publications

(19 citation statements)

References 55 publications

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“…2022). Temporal progression through the hippocampus is also similar between the models, occurring first and primarily in the CA1 and then moving into the DG and CA3 (Britz et al . 2022; Hascup et al .…”

Section: Discussionmentioning

confidence: 78%

“…This divergence could be due to differences between the mouse models including gene overexpression and transgenic versus knock-in genetic manipulation. AβPP/PS1 exhibit greater amyloid burden, higher early attrition rate, and more aggressive cognitive decline (Britz et al . 2022).…”

Section: Discussionmentioning

confidence: 99%

“…2016). Amyloidosis throughout disease progression has been observed as similar between male and female APP NL-F/NL-F mice, while reports of cognitive symptomology yield mixed results (Britz et al . 2022; Kundu et al .…”

Section: Introductionmentioning

confidence: 99%

“…Further, investigation of sex differences for AD mice is limited (Kundu et al . 2021; Britz et al . 2022; Masuda et al .…”

Section: Introductionmentioning

confidence: 99%

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Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice

Findley,

McFadden,

Hill

et al. 2023

Preprint

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It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer’s disease (AD) progression, contributing to negative cognitive outcomes. In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL-F). At 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-Fmale mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-Fmice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-Fmice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-Fmice, but only aged females displayed recognition memory deficits compared to age-matched control mice. These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-Fmice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-Fmice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Further, investigation of sex differences for AD mice is limited (Kundu et al . 2021; Britz et al . 2022; Masuda et al .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice

Findley,

McFadden,

Hill

et al. 2023

Preprint

Self Cite

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“…Deficits in plasticity is typically linked to memory problems. However, despite deficits in plasticity at six months, App NL-F mice have no spatial memory impairment at this age [45]. Other forms of memory have not been explored, prompting us to investigate the possible effect on social memory.…”

Section: Resultsmentioning

confidence: 99%

Early astrocytic dysfunction is associated to mistuned synapses as well as anxiety and depressive-like behavior in the AppNL-F mouse model of Alzheimers disease

Portal,

Sodergren,

Pares i Borrell

et al. 2023

Preprint

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Alzheimers disease is the most common neurodegenerative disease, reported as 75 to 80% of dementia cases worldwide. Unfortunately, there are to date no disease modifying treatments available for this mental illness. It is therefore urgent to identify new pharmacological targets. Alzheimers disease is thought to be caused by important phosphorylation of the microtubule associated protein Tau and abnormal amyloid-beta (A beta) accumulation around brain cells, together causing neurodegeneration. Whether the late phases of the disease are well described, recent evidence suggest synaptic impairments at a pre-A beta plaque stage. However, the underlaying mechanisms remain yet to be clarified. In this study we used the AppNL-F knock-in mouse model of Alzheimers disease which carries two disease-causing mutations inserted in the amyloid precursor protein (App) gene and shows pathological A beta plaques not earlier than fifteen months of age. To better understand early changes, we investigated in six months old animals, synaptic plasticity, and its potential pharmacological targeting in the treatment of this pathology. Our electrophysiological recordings revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a higher apathy-like and depression-like behavior. Interestingly, a single injection of ketamine (5mg/kg), twenty-four hours prior to experiment, partially corrected synaptic and depression-like behavior observed in six months old animals, compared to non-treated controls. In contrast with the amyloid-hypothesis of Alzheimers disease, our study shows that earlier synaptic impairments could at least in part be the cause of the later-on observed symptoms, which could be prevented by pharmacological intervention.

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Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice

Fang,

Peck,

Quinn

et al. 2024

GeroScience

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Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer’s disease (AD). The APPNL−F/NL−F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL−F/NL−F mice. Thus, 4-month-old male and female APPNL−F/NL−F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APPNL−F/NL−F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-β (Aβ)42 and senescence-associated-β-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL−F/NL−F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine. Graphical Abstract

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Assessing Sex-Specific Circadian, Metabolic, and Cognitive Phenotypes in the AβPP/PS1 and APPNL-F/NL-F Models of Alzheimer’s Disease

Cited by 9 publications

References 55 publications

Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice

Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice

Early astrocytic dysfunction is associated to mistuned synapses as well as anxiety and depressive-like behavior in the AppNL-F mouse model of Alzheimers disease

Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice

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