Sex differences in metabolic phenotype and hypothalamic inflammation in the 3xTg-AD mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is notably associated with cognitive decline resulting from impaired function of hippocampal and cortical areas; however, several other domains and corresponding brain regions are affected. One such brain region is the hypothalamus, shown to atrophy and develop amyloid and tau pathology in AD patients. The hypothalamus controls several functions necessary for survival, including energy and glucose homeostasis. Changes in appetite and body weight are common in AD, often seen several years prior to the onset of cognitive symptoms. Therefore, altered metabolic processes may serve as a biomarker for AD, as well as a target for treatment, considering they are likely both a result of pathological changes and contributor to disease progression. Previously, we reported sexually dimorphic metabolic disturbances in ~ 7-month-old 3xTg-AD mice, accompanied by differences in systemic and hypothalamic inflammation. METHODS: In the current study, we investigated metabolic outcomes and hypothalamic inflammation in 3xTg-AD males and females at 3, 6, 9, and 12 months of age to determine when these sex differences emerge. RESULTS: In agreement with our previous study, AD males displayed less weight gain and adiposity, as well as reduced blood glucose levels following a glucose challenge, compared to females. These trends were apparent by 6-9 months of age, coinciding with increased expression of inflammatory markers (Iba1, GFAP, TNF-α, and IL-1ß) in the hypothalamus of AD males. CONCLUSIONS: These findings provide additional evidence for sex-dependent effects of AD pathology on energy and glucose homeostasis, which may be linked to hypothalamic inflammation.

Alzheimer's disease (AD), often associated with memory loss, can also affect other parts of the brain and body, resulting in several other symptoms. Changes in appetite and body weight are commonly seen in people with AD, often before they start showing signs of memory loss. These metabolism-related changes are likely due in part to AD affecting a part of the brain called the hypothalamus, which controls important functions like energy balance (calories in vs. calories out) and blood sugar levels. This study aimed to examine whether changes in metabolism and the hypothalamus could serve as early signs of AD, and even help in treating the disease. We also wanted to see if these changes were influenced by biological sex, as two-thirds of AD patients are women, and our previous studies showed many differences between males and females. In this study, we observed male and female mice at different ages to see when these changes began to appear. We found that male AD mice gained less weight, had less body fat, and had better blood sugar control, compared to female AD mice. These differences became noticeable at the same age that we noticed signs of increased inflammation in the hypothalamus of male mice. These findings suggest that AD affects males and females differently, particularly in terms of energy balance and blood sugar control, and this might be related to inflammation in the hypothalamus. This research could provide valuable insights into understanding, diagnosing, and treating Alzheimer's disease.

Menopause causes metabolic and cognitive impairments in a chronic cerebral hypoperfusion model of vascular contributions to cognitive impairment and dementia.

BACKGROUND: The vast majority of women with dementia are post-menopausal. Despite clinical relevance, menopause is underrepresented in rodent models of dementia. Before menopause, women are less likely than men to experience strokes, obesity, and diabetes-known risk factors for vascular contributions to cognitive impairment and dementia (VCID). During menopause, ovarian estrogen production stops and the risk of developing these dementia risk factors spikes. Here, we aimed to determine if menopause worsens cognitive impairment in VCID. We hypothesized that menopause would cause metabolic dysfunction and increase cognitive impairment in a mouse model of VCID. METHODS: We performed a unilateral common carotid artery occlusion surgery to produce chronic cerebral hypoperfusion and model VCID in mice. We used 4-vinylcyclohexene diepoxide to induce accelerated ovarian failure and model menopause. We evaluated cognitive impairment using behavioral tests including novel object recognition, Barnes maze, and nest building. To assess metabolic changes, we measured weight, adiposity, and glucose tolerance. We explored multiple aspects of brain pathology including cerebral hypoperfusion and white matter changes (commonly observed in VCID) as well as changes to estrogen receptor expression (which may mediate altered sensitivity to VCID pathology post-menopause). RESULTS: Menopause increased weight gain, glucose intolerance, and visceral adiposity. VCID caused deficits in spatial memory regardless of menopausal status. Post-menopausal VCID specifically led to additional deficits in episodic-like memory and activities of daily living. Menopause did not alter resting cerebral blood flow on the cortical surface (assessed by laser speckle contrast imaging). In the white matter, menopause decreased myelin basic protein gene expression in the corpus callosum but did not lead to overt white matter damage (assessed by Luxol fast blue). Menopause did not significantly alter estrogen receptor expression (ERα, ERß, or GPER1) in the cortex or hippocampus. CONCLUSIONS: Overall, we have found that the accelerated ovarian failure model of menopause caused metabolic impairment and cognitive deficits in a mouse model of VCID. Further studies are needed to identify the underlying mechanism. Importantly, the post-menopausal brain still expressed estrogen receptors at normal (pre-menopausal) levels. This is encouraging for any future studies attempting to reverse the effects of estrogen loss by activating brain estrogen receptors.

Nearly all women with dementia are menopausal. Reduced blood flow to the brain, resulting from damaged blood vessels, can lead to vascular dementia. Vascular dementia is the second most common cause of dementia. Before menopause, women are less likely than men to experience strokes, obesity, and diabetes­known risk factors for vascular dementia. During menopause, estrogen levels drop and the risk of developing these dementia risk factors increases. The goal of this study was to determine how menopause impacts risk factors (obesity, diabetes), memory and brain pathology in vascular dementia. This study used mouse models of vascular dementia and menopause. Menopause increased weight gain and other indicators of poor metabolic health. In mice with vascular dementia, menopausal mice had worse memory than pre-menopausal mice. After menopause, the brain still expressed estrogen receptors at normal (pre-menopausal) levels. This is encouraging for any future studies attempting to reverse the effects of estrogen loss by activating brain estrogen receptors.

Sex differences in the effects of high fat diet on underlying neuropathology in a mouse model of VCID.

BACKGROUND: Damage to the cerebral vasculature can lead to vascular contributions to cognitive impairment and dementia (VCID). A reduction in blood flow to the brain leads to neuropathology, including neuroinflammation and white matter lesions that are a hallmark of VCID. Mid-life metabolic disease (obesity, prediabetes, or diabetes) is a risk factor for VCID which may be sex-dependent (female bias). METHODS: We compared the effects of mid-life metabolic disease between males and females in a chronic cerebral hypoperfusion mouse model of VCID. C57BL/6J mice were fed a control or high fat (HF) diet starting at ~ 8.5 months of age. Three months after diet initiation, sham or unilateral carotid artery occlusion surgery (VCID model) was performed. Three months later, mice underwent behavior testing and brains were collected to assess pathology. RESULTS: We have previously shown that in this VCID model, HF diet causes greater metabolic impairment and a wider array of cognitive deficits in females compared to males. Here, we report on sex differences in the underlying neuropathology, specifically white matter changes and neuroinflammation in several areas of the brain. White matter was negatively impacted by VCID in males and HF diet in females, with greater metabolic impairment correlating with less myelin markers in females only. High fat diet led to an increase in microglia activation in males but not in females. Further, HF diet led to a decrease in proinflammatory cytokines and pro-resolving mediator mRNA expression in females but not males. CONCLUSIONS: The current study adds to our understanding of sex differences in underlying neuropathology of VCID in the presence of a common risk factor (obesity/prediabetes). This information is crucial for the development of effective, sex-specific therapeutic interventions for VCID.

Reduced blood flow to the brain resulting from damaged blood vessels can lead to vascular dementia. Neuroinflammation and white matter damage are characteristics of vascular dementia. Middle-age is a time when obesity and prediabetes can increase risk for vascular dementia. This increase in risk is greater for women. A high fat diet causes obesity and prediabetes in mice. We compared the effects of diet-induced obesity in middle-age between males and females in a mouse model of vascular dementia. We have previously shown that a high fat diet causes greater obesity and prediabetes and a wider array of learning and memory problems in females compared to males. Here, we report on sex differences in the damage to the brain. White matter was negatively impacted by vascular dementia in males and high fat diet in females, with more severe prediabetes correlating with less white matter markers in females only. High fat diet led to an increase in activation of microglia (immune cells in the brain) in males but not in females. High fat diet also led to a decrease in pro-inflammatory and pro-resolving mediators expression in females but not males. The current study adds to our understanding of sex differences in underlying damage to the brain caused by vascular dementia in the presence of common risk factors (obesity and prediabetes). This information is needed for the development of effective, sex-specific treatments for vascular dementia.

High-fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner.

BACKGROUND: Approximately 70% of Alzheimer's disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3× more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. METHODS: Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet from 3 to 7 months of age. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. RESULTS: In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, AD/MxD females had more amyloid beta plaques and hippocampal levels of insoluble amyloid beta 40 and 42 than AD/MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. CONCLUSIONS: High-fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women.