Effects of obesogenic diet and 17β-estradiol in female mice with 3/3, 3/4, and 4/4 genotypes.

The main genetic risk factor for Alzheimer's disease (AD) is the apolipoprotein E ε4 allele (). AD risk associated with disproportionately affects women. Furthermore, human and rodent studies indicate that the cognitive deficits associated with are greater in females.

Apolipoprotein E polymorphisms and female fertility in a transgenic mouse model of Alzheimer's disease.

Apolipoprotein E (APOE) is a major cholesterol carrier responsible for lipid transport and injury repair in the brain. The human APOE gene (h-APOE) has 3 naturally occurring alleles: ε3, the common allele; ε4, which increases Alzheimer's disease (AD) risk up to 15-fold; and ε2, the rare allele which protects against AD. Although APOE4 has negative effects on neurocognition in old age, its persistence in the population suggests a survival advantage.

Protection against -associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice.

The apolipoprotein ε4 allele ( ) is associated with decreased longevity, increased vulnerability to age-related declines, and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of -associated aging phenotypes. Here we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against age-related impairments in versus the predominant genotype using early middle-aged mice with knock-in of human alleles.

Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology.

The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial-derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity.

Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity.

Obesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer's disease (AD) and vascular dementia. Obesity is also characterized by chronic, low-grade inflammation that is implicated in mediating negative consequences body-wide. Toll-like receptor 4 (TLR4) signaling from peripheral macrophages is implicated as an essential regulator of the systemic inflammatory effects of obesity.

Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

Background: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures.

Iron associated lipid peroxidation in Alzheimers disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice.

Iron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimers disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death. To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed postmortem human brain and ApoEFAD mice.

Effects of Genotype and Western Diet on Metabolic Phenotypes in Female Mice.

Western diets high in sugars and saturated fats have been reported to induce metabolic and inflammatory impairments that are associated with several age-related disorders, including Alzheimer's disease (AD) and type 2 diabetes (T2D). The apolipoprotein E () genotype is associated with metabolic and inflammatory outcomes that contribute to risks for AD and T2D, with the genotype increasing risks relative to the more common allele. In this study, we investigated the impacts of the genotype on systemic and neural effects of the Western diet.

Role of estrogen in women's Alzheimer's disease risk as modified by APOE.

Alzheimer's disease (AD) is characterized by numerous sexual dimorphisms that impact the development, progression, and probably the strategies to prevent and treat the most common form of dementia. In this review, we consider this topic from a female perspective with a specific focus on how women's vulnerability to the disease is affected by the individual and interactive effects of estrogens and apolipoprotein E (APOE) genotype. Importantly, APOE appears to modulate systemic and neural outcomes of both menopause and estrogen-based hormone therapy.

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models.

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2).

Androgens Regulate Tau Phosphorylation Through Phosphatidylinositol 3-Kinase-Protein Kinase B-Glycogen Synthase Kinase 3β Signaling.

Age-related testosterone depletion in men is a risk factor for Alzheimer's disease (AD). How testosterone modulates AD risk remains to be fully elucidated, although regulation of tau phosphorylation has been suggested as a contributing protective action. To investigate the relationship between testosterone and tau phosphorylation, we first evaluated the effect of androgen status on tau phosphorylation in 3xTg-AD mice.

Microglial transcription profiles in mouse and human are driven by APOE4 and sex.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 is known to affect the function of microglia, but to what extent this gene drives microglial gene expression has thus far not been examined. Using a transgenic mouse model of AD that expresses human APOE, we identify a unique transcriptional profile associated with APOE4 expression.

Second to fourth digit ratio (2D:4D) is associated with dementia in women.

Alzheimer's disease is characterized by sex differences that may involve sex hormone exposure during development. Finger length ratios, an indirect measure of prenatal androgen exposure, were found to significantly differ in women with and without dementia. This finding links a relatively feminine in utero development with vulnerability to dementia in women.

Dementia risk in women higher in same-sex than opposite-sex twins.

Introduction: Hormones may be one possible mechanism underlying sex differences in dementia incidence. We examined whether presumed differential prenatal hormone milieu is related to dementia risk by comparing dementia rates in same- and opposite-sex dizygotic twin pairs in male and female twins.

Methods: The sample comprised 43,254 individuals from dizygotic twin pairs aged 60 and older from the Swedish Twin Registry.

Aging Reduces Estradiol Protection Against Neural but Not Metabolic Effects of Obesity in Female 3xTg-AD Mice.

Vulnerability to Alzheimer's disease (AD) is increased by several risk factors, including midlife obesity, female sex, and the depletion of estrogens in women as a consequence of menopause. Conversely, estrogen-based hormone therapies have been linked with protection from age-related increases in adiposity and dementia risk, although treatment efficacy appears to be affected by the age of initiation. Potential interactions between obesity, AD, aging, and estrogen treatment are likely to have significant impact on optimizing the use of hormone therapies in postmenopausal women.

Staining and Quantification of β-Amyloid Pathology in Transgenic Mouse Models of Alzheimer's Disease.

Studies of Alzheimer's disease (AD) using experimental systems most often involve transgenic mouse models that are characterized by neural accumulation of β-amyloid protein (Aβ), which is widely hypothesized to have a key role in AD pathogenesis. Quantification of Aβ in transgenic mice typically is accomplished through both biochemical and histochemical approaches. In this chapter, we describe two techniques for the histological detection of Aβ, immunostaining with Aβ antibodies and staining with the amyloid dye thioflavin S, and its quantification using digital imaging.

APOE genotype affects metabolic and Alzheimer-related outcomes induced by Western diet in female EFAD mice.

Development of Alzheimer's disease (AD) is regulated by interactive effects of genetic and environmental risk factors. The most significant genetic risk factor for AD is the ε4 allele of apolipoprotein E ( APOE4), which has been shown to exert greater AD risk in women. An important modifiable AD risk factor is obesity and its associated metabolic dysfunctions.

TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity.

Background: Obesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer's disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling.

Effects of aging, high-fat diet, and testosterone treatment on neural and metabolic outcomes in male brown Norway rats.

Risk for Alzheimer's disease (AD) is affected by multiple factors, including aging, obesity, and low testosterone. We previously showed that obesity and low testosterone independently and interactively exacerbate AD-related outcomes in young adult rodents. The goals of the present study are two-fold: to examine whether the effects of an obesogenic diet differ with increasing age and to determine if testosterone treatment in middle-aged and aged animals mitigates negative effects of the diet.

Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans.

Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice.

TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice.

Alzheimer's disease (AD) pathogenesis is a multifactorial process that involves numerous pathways within the central nervous system. Thus, interventions that interact with several disease-related pathways may offer an increased opportunity for successful prevention and treatment of AD. Translocator protein 18 kD (TSPO) is a mitochondrial protein that is associated with regulation of many cellular processes including inflammation, steroid synthesis, apoptosis, and mitochondrial respiration.

The Oxygen Paradox, the French Paradox, and age-related diseases.

A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen "a toxic environmental poison" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.

Obesity Accelerates Alzheimer-Related Pathology in but not Mice.

Alzheimer's disease (AD) risk is modified by both genetic and environmental risk factors, which are believed to interact to cooperatively modify pathogenesis. Although numerous genetic and environmental risk factors for AD have been identified, relatively little is known about potential gene-environment interactions in regulating disease risk. The strongest genetic risk factor for late-onset AD is the ε4 allele of apolipoprotein E (4).

Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice.

Depletion of ovarian hormones at menopause is associated with increased Alzheimer's disease (AD) risk. Hormone loss also increases central adiposity, which promotes AD development. One strategy to improve health outcomes in postmenopausal women is estrogen-based hormone therapy (HT), though its efficacy is controversial.

Sex and the development of Alzheimer's disease.

Men and women exhibit differences in the development and progression of Alzheimer's disease (AD). The factors underlying the sex differences in AD are not well understood. This Review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD.