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1.
Horm Behav ; 164: 105594, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38917776

RESUMEN

Menopause is an endocrine shift leading to increased vulnerability for cognitive impairment and dementia risk factors, in part due to loss of neuroprotective circulating estrogens. Systemic replacement of estrogen post-menopause has limitations, including risk for estrogen-sensitive cancers. A promising therapeutic approach therefore might be to deliver estrogen only to the brain. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in ovariectomized mice (a surgical menopause model). We treated mice with the prodrug 10ß,17ß-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17ß-estradiol only in the brain. Young and middle-aged C57BL/6 J mice received ovariectomy and subcutaneous implant containing vehicle or DHED and underwent cognitive testing to assess memory after 1-3.5 months of treatment. Low and medium doses of DHED did not alter metabolic status in middle-aged mice. In both age groups, DHED treatment improved spatial memory in ovariectomized mice. Additional testing in middle-aged mice showed that DHED treatment improved working and recognition memory in ovariectomized mice. These results lay the foundation for future studies determining if this intervention is as efficacious in models of dementia with comorbid risk factors.

2.
J Neuroinflammation ; 19(1): 110, 2022 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-35568928

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia Vascular , Estado Prediabético , Actividades Cotidianas , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Placa Amiloide , Estado Prediabético/complicaciones
3.
FASEB J ; 34(11): 15108-15122, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32939871

RESUMEN

Mid-life metabolic disease (ie, obesity, diabetes, and prediabetes) causes vascular dysfunction and is a risk factor for vascular contributions to cognitive impairment and dementia (VCID), particularly in women. Using middle-aged mice, we modeled metabolic disease (obesity/prediabetes) via chronic high-fat (HF) diet and modeled VCID via unilateral common carotid artery occlusion. VCID impaired spatial memory in both sexes, but episodic-like memory in females only. HF diet caused greater weight gain and glucose intolerance in middle-aged females than males. HF diet alone impaired episodic-like memory in both sexes, but spatial memory in females only. Finally, the combination of HF diet and VCID elicited cognitive impairments in all tests, in both sexes. Sex-specific correlations were found between metabolic outcomes and memory. Notably, both visceral fat and the pro-inflammatory cytokine tumor necrosis factor alpha correlated with spatial memory deficits in middle-aged females, but not males. Overall, our data show that HF diet causes greater metabolic impairment and a wider array of cognitive deficits in middle-aged females than males. The combination of HF diet with VCID elicits deficits across multiple cognitive domains in both sexes. Our data are in line with clinical data, which shows that mid-life metabolic disease increases VCID risk, particularly in females.


Asunto(s)
Disfunción Cognitiva/etiología , Demencia Vascular/complicaciones , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Memoria Espacial , Animales , Disfunción Cognitiva/patología , Femenino , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Factores Sexuales
4.
J Neuroinflammation ; 17(1): 285, 2020 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-32993686

RESUMEN

BACKGROUND: Hypothalamic dysfunction occurs early in the clinical course of Alzheimer's disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observed years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high-fat diet and metabolic disease (e.g., obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex. METHODS: WT and 3xTg-AD male and female mice were fed a control (10% fat) or high-fat (HF 60% fat) diet from ~ 3-7 months of age, then tested for metabolic and hypothalamic disturbances. RESULTS: On control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-α, IL-1ß). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1ß, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group. CONCLUSIONS: These findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Glucemia/metabolismo , Dieta Alta en Grasa/efectos adversos , Hipotálamo/metabolismo , Enfermedades Metabólicas/metabolismo , Caracteres Sexuales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Glucemia/genética , Femenino , Hipotálamo/patología , Masculino , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/patología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología
5.
PLoS Genet ; 13(11): e1007049, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29107990

RESUMEN

The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5α-dihydrotestosterone (5α-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis.


Asunto(s)
Andrógenos/fisiología , Encéfalo/efectos de los fármacos , Vaina de Mielina/efectos de los fármacos , Receptores Androgénicos/metabolismo , Diferenciación Sexual , Antagonistas de Receptores Androgénicos/farmacología , Animales , Animales Recién Nacidos , Encéfalo/fisiología , Dihidrotestosterona/farmacología , Femenino , Flutamida/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/fisiología
6.
Int J Mol Sci ; 21(9)2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32365806

RESUMEN

Progesterone and testosterone, beyond their roles as sex hormones, are neuroactive steroids, playing crucial regulatory functions within the nervous system. Among these, neuroprotection and myelin regeneration are important ones. The present review aims to discuss the stimulatory effects of progesterone and testosterone on the process of myelination and remyelination. These effects have been demonstrated in vitro (i.e., organotypic cultures) and in vivo (cuprizone- or lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE)). Both steroids stimulate myelin formation and regeneration by acting through their respective intracellular receptors: progesterone receptors (PR) and androgen receptors (AR). Activation of these receptors results in multiple events involving direct transcription and translation, regulating general homeostasis, cell proliferation, differentiation, growth and myelination. It also ameliorates immune response as seen in the EAE model, resulting in a significant decrease in inflammation leading to a fast recovery. Although natural progesterone and testosterone have a therapeutic potential, their synthetic derivatives-the 19-norprogesterone (nestorone) and 7α-methyl-nortestosterone (MENT), already used as hormonal contraception or in postmenopausal hormone replacement therapies, may offer enhanced benefits for myelin repair. We summarize here a recent advancement in the field of myelin biology, to treat demyelinating disorders using the natural as well as synthetic analogs of progesterone and testosterone.


Asunto(s)
Sistema Nervioso Central/metabolismo , Vaina de Mielina/metabolismo , Progesterona/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Progesterona/metabolismo , Testosterona/metabolismo , Andrógenos/metabolismo , Animales , Biomarcadores , Susceptibilidad a Enfermedades , Hormonas Esteroides Gonadales/metabolismo , Humanos , Oligodendroglía/metabolismo
7.
Glia ; 67(12): 2248-2263, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31328333

RESUMEN

The fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage-gated sodium channels at nodes of Ranvier. Axo-glial communication is required for assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation. In addition, the formation of early nodal protein clusters (or prenodes) along axons prior to myelination has been reported, and can be induced by oligodendrocyte conditioned medium (OCM). Our recent work on cultured hippocampal neurons showed that OCM-induced prenodes are associated with an increased conduction velocity (Freeman et al., 2015). We here unravel the nature of the oligodendroglial secreted factors. Mass spectrometry analysis of OCM identified several candidate proteins (i.e., Contactin-1, ChL1, NrCAM, Noelin2, RPTP/Phosphacan, and Tenascin-R). We show that Contactin-1 combined with RPTP/Phosphacan or Tenascin-R induces clusters of nodal proteins along hippocampal GABAergic axons. Furthermore, Contactin-1-immunodepleted OCM or OCM from Cntn1-null mice display significantly reduced clustering activity, that is restored by addition of soluble Contactin-1. Altogether, our results identify Contactin-1 secreted by oligodendrocytes as a novel factor that may influence early steps of nodal sodium channel cluster formation along specific axon populations.


Asunto(s)
Contactina 1/metabolismo , Hipocampo/metabolismo , Proteína Nodal/metabolismo , Oligodendroglía/metabolismo , Animales , Células Cultivadas , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Contactina 1/genética , Neuronas GABAérgicas/metabolismo , Hipocampo/citología , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína Nodal/genética , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Ratas Wistar
8.
Proc Natl Acad Sci U S A ; 113(51): 14829-14834, 2016 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-27930320

RESUMEN

Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP)+ and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0)+ and peripheral myelin protein 22-kDa (PMP22)+ myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-ketosteroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.


Asunto(s)
Vaina de Mielina/metabolismo , Receptores Androgénicos/metabolismo , Remielinización , Andrógenos/metabolismo , Animales , Astrocitos/citología , Astrocitos/metabolismo , Sistema Nervioso Central/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Fluorescente , Neuroglía/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Receptores de Esteroides/metabolismo , Células de Schwann/metabolismo , Transducción de Señal , Testículo/metabolismo , Testosterona/metabolismo
9.
Acta Neuropathol Commun ; 12(1): 18, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38291527

RESUMEN

In men, reduced levels of testosterone are associated with the prevalence and progression of multiple sclerosis (MS), a chronic and disabling demyelinating disorder. Testosterone has been shown to promote myelin repair. Here, we demonstrate that the cooperation between testosterone and CXCR4 signaling involving astrocytes is required for myelin regeneration after focal demyelination produced in the ventral mouse spinal cord by the infusion of lysolecithin. The testosterone-dependent remyelination of axons by oligodendrocytes was accompanied by an increase in astrocytes expressing CXCR4, its ligand CXCL12 and the androgen receptor (AR) within the demyelinated area. Depriving males of their testosterone or pharmacological inhibition of CXCR4, with the selective antagonist AMD3100, prevented the appearance of astrocytes expressing CXCR4, CXCL12 and AR within the demyelinated area and the concomitant recruitment of myelin forming oligodendrocytes. Conditional genetic ablation of either CXCR4 or AR in astrocytes also completely blocked the formation of new myelin by oligodendrocytes. Interestingly, the gain of function mutation in CXCR4 causing WHIM syndrome allows remyelination to take place, even in the absence of testosterone, but its potentiating effects remained observable. After testosterone deprivation or CXCR4 inhibition, the absence of astrocytes within the demyelinated area led to the incursion of Schwann cells, most likely derived from spinal nerves, and the formation of peripheral nerve type myelin. In patients with progressive MS, astrocytes expressing CXCR4 and AR surrounded myelin lesions, and their presence opposed the incursion of Schwann cells. These results highlight a mechanism of promyelinating testosterone signaling and the importance of normalizing its levels in combined myelin repair therapies.


Asunto(s)
Andrógenos , Vaina de Mielina , Humanos , Ratones , Masculino , Animales , Vaina de Mielina/patología , Andrógenos/farmacología , Células de Schwann , Oligodendroglía/patología , Testosterona , Médula Espinal/patología , Receptores CXCR4
10.
bioRxiv ; 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38293070

RESUMEN

Menopause accelerates metabolic dysfunction, including (pre-)diabetes, obesity and visceral adiposity. However, the effects of endocrine vs. chronological aging in this progression are poorly understood. We hypothesize that menopause, especially in the context of middle-age, will exacerbate the metabolic effects of a high fat diet. Using young-adult and middle-aged C57BL/6J female mice, we modeled diet-induce obesity via chronic administration of high fat (HF) diet vs. control diet. We modeled peri-menopause/menopause via injections of 4-vinylcyclohexene diepoxide, which accelerates ovarian failure vs. vehicle. We performed glucose tolerance tests 2.5 and 7 months after diet onset, during the peri-menopausal and menopausal phases, respectively. Peri-menopause increased the severity of glucose intolerance and weight gain in middle-aged, HF-fed mice. Menopause increased weight gain in all mice regardless of age and diet, while chronological aging drove changes in adipose tissue distribution towards more visceral vs. subcutaneous adiposity. These data are in line with clinical data showing that post-menopausal women are more susceptible to metabolic dysfunction and suggest that greater chorological age exacerbates the effects of endocrine aging (menopause). This work highlights the importance of considering both chronological and endocrine aging in studies of metabolic health.

11.
Biol Sex Differ ; 14(1): 51, 2023 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-37559092

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer , Ratones , Femenino , Masculino , Animales , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Caracteres Sexuales , Proteínas tau , Ratones Transgénicos , Hipotálamo/metabolismo , Fenotipo , Inflamación , Glucosa
12.
Biol Sex Differ ; 14(1): 34, 2023 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-37221553

RESUMEN

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.


Asunto(s)
Isquemia Encefálica , Disfunción Cognitiva , Demencia , Femenino , Humanos , Masculino , Animales , Ratones , Receptores de Estrógenos , Actividades Cotidianas , Menopausia , Estrógenos , Obesidad
13.
bioRxiv ; 2023 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-37609180

RESUMEN

Menopause is a major endocrinological shift that leads to an increased vulnerability to the risk factors for cognitive impairment and dementia. This is thought to be due to the loss of circulating estrogens, which exert many potent neuroprotective effects in the brain. Systemic replacement of estrogen post-menopause has many limitations, including increased risk for estrogen-sensitive cancers. A more promising therapeutic approach therefore might be to deliver estrogen only to the brain thus limiting adverse peripheral side effects. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in post-menopausal mice. We modeled surgical menopause via bilateral ovariectomy (OVX). We treated mice with the pro-drug 10ß,17ß-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17ß-estradiol only in the brain. Young (2.5-month) and middle-aged (11-month-old) female C57BL/6J mice received ovariectomy and a subcutaneous implant containing vehicle (cholesterol) or DHED. At 3.5 months old (young group) and 14.5 months old (middle-aged group), mice underwent behavior testing to assess memory. DHED did not significantly alter metabolic status in middle-aged, post-menopausal mice. In both young and middle-aged mice, the brain-specific estrogen DHED improved spatial memory. Additional testing in middle-aged mice also showed that DHED improved working and recognition memory. These promising results lay the foundation for future studies aimed at determining if this intervention is as efficacious in models of dementia that have comorbid risk factors.

14.
Biol Sex Differ ; 14(1): 31, 2023 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-37208759

RESUMEN

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.


Asunto(s)
Disfunción Cognitiva , Demencia Vascular , Estado Prediabético , Femenino , Ratones , Masculino , Animales , Dieta Alta en Grasa , Enfermedades Neuroinflamatorias , Caracteres Sexuales , Estado Prediabético/complicaciones , Ratones Endogámicos C57BL , Demencia Vascular/complicaciones , Demencia Vascular/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Obesidad
15.
Front Cell Neurosci ; 16: 908401, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36072569

RESUMEN

The destruction of the myelin sheath that encircles axons leads to impairments of nerve conduction and neuronal dysfunctions. A major demyelinating disorder is multiple sclerosis (MS), a progressively disabling disease in which immune cells attack the myelin. To date, there are no therapies to target selectively myelin lesions, repair the myelin or stop MS progression. Small peptides recognizing epitopes selectively exposed at sites of injury show promise for targeting therapeutics in various pathologies. Here we show the selective homing of the four amino acid peptide, cysteine-alanine-lysine glutamine (CAQK), to sites of demyelinating injuries in three different mouse models. Homing was assessed by administering fluorescein amine (FAM)-labeled peptides into the bloodstream of mice and analyzing sites of demyelination in comparison with healthy brain or spinal cord tissue. FAM-CAQK selectively targeted demyelinating areas in all three models and was absent from healthy tissue. At lesion sites, the peptide was primarily associated with the fibrous extracellular matrix (ECM) deposited in interstitial spaces proximal to reactive astrocytes. Association of FAM-CAQK was detected with tenascin-C although tenascin depositions made up only a minor portion of the examined lesion sites. In mice on a 6-week cuprizone diet, FAM-CAQK peptide crossed the nearly intact blood-brain barrier and homed to demyelinating fiber tracts. These results demonstrate the selective targeting of CAQK to demyelinating injuries under multiple conditions and confirm the previously reported association with the ECM. This work sets the stage for further developing CAQK peptide targeting for diagnostic and therapeutic applications aimed at localized myelin repair.

16.
Biol Sex Differ ; 11(1): 35, 2020 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-32605602

RESUMEN

Androgens affect the cerebral vasculature and may contribute to sex differences in cerebrovascular diseases. Men are at a greater risk for stroke and vascular contributions to cognitive impairment and dementia (VCID) compared to women throughout much of the lifespan. The cerebral vasculature is a target for direct androgen actions, as it expresses several sex steroid receptors and metabolizing enzymes. Androgens' actions on the cerebral vasculature are complex, as they have been shown to have both protective and detrimental effects, depending on factors such as age, dose, and disease state. When administered chronically, androgens are shown to be pro-angiogenic, promote vasoconstriction, and influence blood-brain barrier permeability. In addition to these direct effects of androgens on the cerebral vasculature, androgens also influence other vascular risk factors that may contribute to sex differences in cerebrovascular diseases. In men, low androgen levels have been linked to metabolic and cardiovascular diseases including hypertension, diabetes, hyperlipidemia, and obesity, which greatly increase the risk of stroke and VCID. Thus, a better understanding of androgens' interactions with the cerebral vasculature under physiological and pathological conditions is of key importance.


Asunto(s)
Andrógenos/fisiología , Circulación Cerebrovascular , Trastornos Cerebrovasculares/fisiopatología , Animales , Vasos Sanguíneos/fisiología , Humanos
17.
eNeuro ; 7(1)2020.
Artículo en Inglés | MEDLINE | ID: mdl-31871124

RESUMEN

Adult hippocampal neurogenesis (AHN) is suppressed by high-fat (HF) diet and metabolic disease, including obesity and type 2 diabetes. Deficits in AHN may contribute to cognitive decline and increased risk of dementia and mood disorders, which have higher prevalence in women. However, sex differences in the effects of HF diet/metabolic disease on AHN have yet to be thoroughly investigated. Herein, male and female C57BL/6J mice were fed an HF or control (CON) diet from ∼2 to 6 months of age. After 3 months on the diet, mice were injected with 5-ethynyl-2'-deoxyuridine (EdU) then killed 4 weeks later. Cell proliferation, differentiation/maturation, and survival of new neurons in the dentate gyrus were assessed with immunofluorescence for EdU, Ki67, doublecortin (DCX), and NeuN. CON females had more proliferating cells (Ki67+) and neuroblasts/immature neurons (DCX+) compared with CON males; however, HF diet reduced these cells in females to the levels of males. Diet did not affect neurogenesis in males. Further, the numbers of proliferating cells and immature neurons were inversely correlated with both weight gain and glucose intolerance in females only. These effects were robust in the dorsal hippocampus, which supports cognitive processes. Assessment of microglia in the dentate gyrus using immunofluorescence for Iba1 and CD68 uncovered sex-specific effects of diet, which may contribute to observed differences in neurogenesis. These findings demonstrate sex-specific effects of HF diet/metabolic disease on AHN, and highlight the potential for targeting neurogenic deficits to treat cognitive decline and reduce the risk of dementia associated with these conditions, particularly in females.


Asunto(s)
Diabetes Mellitus Tipo 2 , Dieta Alta en Grasa , Animales , Giro Dentado , Dieta Alta en Grasa/efectos adversos , Proteína Doblecortina , Femenino , Hipocampo , Masculino , Ratones , Ratones Endogámicos C57BL , Neurogénesis , Obesidad
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