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Since brain glucose hypometabolism is a feature of Alzheimer’s disease (AD) progression, lactate utilization as an energy source may become critical to maintaining central bioenergetics. We have previously shown that soluble amyloid-β (Aβ) 42 stimulates glutamate release through the α7 nicotinic acetylcholine receptor (α7nAChR) and hippocampal glutamate levels are elevated in the APP/PS1 mouse model of AD. Accordingly, we hypothesized that increased glutamate clearance contributes to elevated extracellular lactate levels through activation of the astrocyte neuron lactate shuttle (ANLS). We utilized an enzyme-based microelectrode array (MEA) selective for measuring basal and phasic extracellular hippocampal lactate in male and female C57BL/6J mice. Although basal lactate was similar, transient lactate release varied across hippocampal subregions with the CA1 > CA3 > dentate for both sexes. Local application of Aβ 42 stimulated lactate release throughout the hippocampus of male mice, but was localized to the CA1 of female mice. Coapplication with a nonselective glutamate or lactate transport inhibitor blocked these responses. Expression levels of SLC16A1, lactate dehydrogenase (LDH) A, and B were elevated in female mice which may indicate compensatory mechanisms to upregulate lactate production, transport, and utilization. Enhancement of the ANLS by Aβ 42 -stimulated glutamate release during AD progression may contribute to bioenergetic dysfunction in AD.

Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex‐specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life‐stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex‐aware, personalized approaches to AD prevention and treatment. By integrating hormone–immune interactions with genetic and glial biology, this review emphasizes the critical need for sex‐specific models in AD research. Highlights Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD). Glial activation is adapted by estrogens to shape vulnerability or resilience to AD. Sex differences in innate and adaptive immunity could contribute to AD progression. Effects of menopausal hormone therapy on immunity in AD remain understudied. Future studies to explore sex differences in immune function during AD are needed. Conceptual framework for sex‐specific Alzheimer's disease (AD) risk. Sex differences in AD vulnerability arise from the intersection of multiple biological systems. Fluctuations in sex hormones across reproductive life stages (e.g., pregnancy, menopause) shape long‐term neuroendocrine tone. These hormonal shifts influence immune modulation, including both peripheral and central immune activity, particularly in glial cells such as microglia and astrocytes. Concurrently, genetic architecture, including sex‐interacting variants such as apolipoprotein E ε4, modifies susceptibility to AD pathology. The dynamic interplay among these systems contributes to a sex‐specific trajectory of AD risk, with distinct implications for disease onset, progression, and therapeutic response in women. (Figure created with BioRender.)

Our previous research demonstrated that soluble amyloid-β (Aβ) 42 , elicits presynaptic glutamate release. We hypothesized that accumulation and deposition of Aβ altered glutamatergic neurotransmission in a temporally and spatially dependent manner. To test this hypothesis, a glutamate selective microelectrode array (MEA) was used to monitor dentate (DG), CA3, and CA1 hippocampal extracellular glutamate levels in 2–4, 6–8, and 18–20 month-old male AβPP/PS1 and age-matched C57BL/6J control mice. Starting at 6 months of age, AβPP/PS1 basal glutamate levels are elevated in all three hippocampal subregions that becomes more pronounced at the oldest age group. Evoked glutamate release was elevated in all three age groups in the DG, but temporally delayed to 18–20 months in the CA3 of AβPP/PS1 mice. However, CA1 evoked glutamate release in AβPP/PS1 mice was elevated at 2–4 months of age and declined with age. Plaque deposition was anatomically aligned (but temporally delayed) with elevated glutamate levels; whereby accumulation was first observed in the CA1 and DG starting at 6–8 months that progressed throughout all hippocampal subregions by 18–20 months of age. The temporal hippocampal glutamate changes observed in this study may serve as a biomarker allowing for time point specific therapeutic interventions in Alzheimer’s disease patients.

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 Alzheimer's 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°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°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-β (Aβ) . 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.

Since brain glucose hypometabolism is a feature of Alzheimer's disease (AD) progression, lactate utilization as an energy source may become critical to maintaining central bioenergetics. We have previously shown that soluble amyloid-β (Aβ) stimulates glutamate release through the α7 nicotinic acetylcholine receptor (α7nAChR) and hippocampal glutamate levels are elevated in the APP/PS1 mouse model of AD. Accordingly, we hypothesized that increased glutamate clearance contributes to elevated extracellular lactate levels through activation of the astrocyte neuron lactate shuttle (ANLS). We utilized an enzyme-based microelectrode array (MEA) selective for measuring basal and phasic extracellular hippocampal lactate in male and female C57BL/6J mice. Although basal lactate was similar, transient lactate release varied across hippocampal subregions with the CA1 > CA3 > dentate for both sexes. Local application of Aβ stimulated lactate release throughout the hippocampus of male mice, but was localized to the CA1 of female mice. Coapplication with a nonselective glutamate or lactate transport inhibitor blocked these responses. Expression levels of SLC16A1, lactate dehydrogenase (LDH) A, and B were elevated in female mice which may indicate compensatory mechanisms to upregulate lactate production, transport, and utilization. Enhancement of the ANLS by Aβ -stimulated glutamate release during AD progression may contribute to bioenergetic dysfunction in AD.

Reliable knowledge of the status and trend of carnivore populations is critical to their conservation and management. Methods for monitoring carnivores, however, are challenging to conduct across large spatial scales. In the Northern Rocky Mountains, wildlife managers need a time- and cost-efficient method for monitoring gray wolf (Canis lupus) populations. Montana Fish, Wildlife and Parks (MFWP) conducts annual telephone surveys of >50,000 deer and elk hunters. We explored how survey data on hunters' sightings of wolves could be used to estimate the occupancy and distribution of wolf packs and predict their abundance in Montana for 2007-2009. We assessed model utility by comparing our predictions to MFWP minimum known number of wolf packs. We minimized false positive detections by identifying a patch as occupied if 2-25 wolves were detected by ≥3 hunters. Overall, estimates of the occupancy and distribution of wolf packs were generally consistent with known distributions. Our predictions of the total area occupied increased from 2007 to 2009 and predicted numbers of wolf packs were approximately 1.34—1.46 times the MFWP minimum counts for each year of the survey. Our results indicate that multi-season occupancy models based on public sightings can be used to monitor populations and changes in the spatial distribution of territorial carnivores across large areas where alternative methods may be limited by personnel, time, accessibility, and budget constraints.

Territoriality in animals is of both theoretical and conservation interest. Animals are territorial when benefits of exclusive access to a limiting resource outweigh costs of maintaining and defending it. The size of territories can be considered a function of ecological factors that affect this benefit–cost ratio. Previous research has shown that territory sizes for wolves (Canis lupus) are largely determined by available biomass of prey, and possibly pack size and density of neighboring wolf packs, but has not been interpreted in a benefit–cost framework. Such a framework is relevant for wolves living in the Northern Rocky Mountains where conflicts with humans increase mortality, thereby potentially increasing costs of being territorial and using prey resources located near humans. We estimated territory sizes for 38 wolf packs in Montana from 2008 to 2009 using 90% adaptive kernels. We then created generalized linear models (GLMs) representing combinations of ecological factors hypothesized to affect the territory sizes of wolf packs. Our top GLM, which had good model fit (R2  =  0.68, P < 0.0005), suggested that territory sizes of wolves in Montana were positively related to terrain ruggedness, lethal controls, and human density and negatively related to number of surrounding packs relative to the size of the territory. We found that the top GLM successfully predicted territory sizes (R2  =  0.53, P < 0.0005) using a jackknife approach. Our study shows that territory sizes of group-living carnivores are influenced by not only intraspecific competition and availability of limiting resources, but also by anthropogenic threats to the group's survival, which could have important consequences where these territorial carnivores come into conflict with humans.