Biology subjects

Hascup, E. R.

Publications and source records attributed to Hascup, E. R..

7 recordsLinked to original sources

bioRxiv2026

D-Methionine Improves Spatial Navigation and Attenuates Oxidative Stress and Amyloid Pathology in a Sex-Specific Manner

BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimers disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD mouse models. MethodsMale and female APP/PS1 and APPNL-F mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic and inflammatory markers, and hippocampal microglial phenotypes were evaluated using biochemical and histological analyses. ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APPNL-F mice. APPNL-F males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APPNL-F mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-{beta} (A{beta})42 in male APP/PS1 mice. Lipid peroxidation, assessed by malondialdehyde, was reduced only in female APPNL-F mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue (pgWAT) IL-6 expression in female APPNL-F mice. In the hippocampus, D-Met remodeled microglial signatures, with female APPNL-F mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression. ConclusionShort-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APPNL-F mice.

neuroscience↗

bioRxiv2025

Surgical Removal of Visceral Adipose Tissue has Therapeutic Benefit in Male APPNL-F Mice

PurposeVisceral white adipose tissue (vWAT) accumulation causes systemic inflammation, insulin resistance, metabolic syndrome, and senescent cell accumulation that are risk factors for Alzheimers disease (AD). Visceral fat removal (VFR) improves metabolism and reduces pro-inflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition. MethodsMale and female APPNL-F mice underwent sham or vWAT surgical resection (periovarian or epididymal and perirenal) at 4 (pre-symptomatic) and 16 (symptomatic) months of age to understand interventional and therapeutic effects, respectively. At 18 months of age, glucose metabolism and novel object recognition (NOR) memory were assayed followed by assessment of body composition and tissue-specific markers of metabolism, cell senescence, inflammation, or amyloid accumulation. ResultsMale and female APPNL-F mice showed distinct VFR responses. In pre-symptomatic males, increased vWAT lipolysis and hepatic lipogenesis led to ectopic liver lipid accumulation, with reduced adiponectin and leptin, elevated visfatin, and impaired glucose metabolism. Symptomatic males showed reduced vWAT lipogenesis, enhanced hepatic lipolysis, glycolysis, and glycogenesis, lowering liver lipids and improving insulin sensitivity. Only symptomatic males improved NOR, linked to elevated hippocampal learning and memory markers. Female vWAT reaccumulation was due to increased lipogenesis and lower lipolysis. Pre-symptomatic females had lower hepatic lipogenesis, while glycolysis and glycogenesis declined with disease progression. Hippocampal senescence and inflammation were elevated early in the disease that persisted symptomatically. ConclusionsSex-specific differences in glucose and lipid metabolism and lipid accumulation underlie the divergent responses to VFR in APPNL-F mice, with symptomatic males showing the only beneficial outcomes in metabolism and cognition. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/669175v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@6ec644org.highwire.dtl.DTLVardef@9ad821org.highwire.dtl.DTLVardef@1e37775org.highwire.dtl.DTLVardef@b7a558_HPS_FORMAT_FIGEXP M_FIG C_FIG Male and female APPNL-F mice exhibited distinct VFR responses to AD progression. In males, early disease stages were marked by vWAT lipolysis and hepatic lipid accumulation with metabolic dysfunction, while symptomatic stages showed a metabolic shift that improved insulin sensitivity and NOR performance. In contrast, females displayed progressive vWAT reaccumulation, reduced hepatic metabolism, and persistent hippocampal senescence and inflammation from early stages onward.

neuroscience↗

bioRxiv2024

Lifespan of male and female APP/PS1 and APPNL-F/NL-F mouse models of Alzheimer's disease

Alzheimers disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APPNL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between within genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in APPNL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports sexual dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

physiology↗

bioRxiv2024

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimers disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30{degrees}C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30{degrees}C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-{beta} (A{beta})42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.

neuroscience↗

bioRxiv2023

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APPNL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimers 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 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, four 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-{beta} (A{beta})42 and senescence associated-{beta}-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.

neuroscience↗

bioRxiv2023

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

BackgroundIt is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimers disease (AD) progression, contributing to negative cognitive outcomes. ObjectiveIn this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL-F). MethodsAt 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. ResultsGlutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice 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-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. ConclusionsThese findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.

neuroscience↗

bioRxiv2021

Sexual dimorphic responses of C57BL/6 mice to Fisetin or Dasatinib and Quercetin cocktail oral treatment

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma and tissue specific markers of senescence-associated secretory phenotype (SASP) and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D+Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Graphical AbstractMale and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Females treated with D+Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. No effects were observed in females treated with Fisetin or males treated with D+Q. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/467509v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d7f450org.highwire.dtl.DTLVardef@e8b32forg.highwire.dtl.DTLVardef@14be597org.highwire.dtl.DTLVardef@1ce31af_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗