Estrogen Signaling in Alzheimer’s Disease: Molecular Insights and Therapeutic Targets for Alzheimer’s Dementia

Uddin, Sahab; Rahman, Motiar; Jakaria, Md.; Rahman, Md. Sohanur; Hossain, Sarwar; Islam, Ariful; Ahmed, Mohiuddin; Mathew, Bijo; Omar, Ulfat M.; Barreto, George E.; Ashraf, Ghulam Md

doi:10.1007/s12035-020-01911-8

Cited by 108 publications

(77 citation statements)

References 177 publications

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“…Oxidized cholesterol species increased in AD brains, 27-hydroxycholesterol (Heverin et al, 2004). Lower estrogen increases the risk of AD (Ratnakumar et al, 2019;Uddin et al, 2020). Increased basal cortisol levels in the plasma of demented individuals (Csernansky et al, 2006).…”

Section: Cholesterol Oxysterols Hormonesmentioning

confidence: 99%

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

2020

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Lipids constitute the bulk of the dry mass of the brain and have been associated with healthy function as well as the most common pathological conditions of the brain. Demographic factors, genetics, and lifestyles are the major factors that influence lipid metabolism and are also the key components of lipid disruption in Alzheimer's disease (AD). Additionally, the most common genetic risk factor of AD, APOE 4 genotype, is involved in lipid transport and metabolism. We propose that lipids are at the center of Alzheimer's disease pathology based on their involvement in the blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, and energy balance. Under healthy conditions, lipid homeostasis bestows a balanced cellular environment that enables the proper functioning of brain cells. However, under pathological conditions, dyshomeostasis of brain lipid composition can result in disturbed BBB, abnormal processing of APP, dysfunction in endocytosis/exocytosis/autophagocytosis, altered myelination, disturbed signaling, unbalanced energy metabolism, and enhanced inflammation. These lipid disturbances may contribute to abnormalities in brain function that are the hallmark of AD. The wide variance of lipid disturbances associated with brain function suggest that AD pathology may present as a complex interaction between several metabolic pathways that are augmented by risk factors such as age, genetics, and lifestyles. Herewith, we examine factors that influence brain lipid composition, review the association of lipids with all known facets of AD pathology, and offer pointers for potential therapies that target lipid pathways.

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Section: Cholesterol Oxysterols Hormonesmentioning

confidence: 99%

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

2020

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“…Many studies have shown that the loss of ovarian hormones in postmenopausal women leads to decreased cognitive function and an increased risk of AD. [ 9,10 ] Estrogen therapy can improve cognition, delay the onset of AD and reduce the risk of AD in postmenopausal women. [ 47,48 ] It has been reported that estrogen promotes the growth and survival of cholinergic neurons and decreases cerebral Aβ deposition.…”

Section: Discussionmentioning

confidence: 99%

“…[ 8 ] According to epidemiologic analyses, nearly two‐thirds of AD patients are women, and the risk of AD is higher in postmenopausal women than in other individuals. [ 9,10 ] Moreover, AD pathology appears to be more likely to present clinically as dementia in females than in males. [ 11 ] AD women display a broader spectrum of dementia‐related behavioral symptoms and experience greater cognitive deterioration than men as the disease progresses.…”

Section: Introductionmentioning

confidence: 99%

“…[ 14 ] Estrogen acts as a neuroprotective agent via estrogen receptor (ER) signaling to reduce the toxicity of Aβ, improve synaptic plasticity, assist initiation of transcription factors and alleviate brain inflammation. [ 10 ] There are two major subtypes of ERs, namely, ERα and ERβ; both receptors are widely distributed in tissues and type‐specific cells in both rodents and humans. [ 15 ] Although both ERs are predominantly expressed in limbic‐related areas in the human brain, the highest expression of ERα mRNA is restricted to the areas such as amygdala and hypothalamus, whereas ERβ mRNA expression is abundant in the areas such as hippocampal formation, cerebral cortex, and thalamus.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxytyrosol Acetate Improves the Cognitive Function of APP/PS1 Transgenic Mice in ERβ‐dependent Manner

Qin

Zhang

et al. 2020

Molecular Nutrition Food Res

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ScopeAlzheimer's disease (AD) is the most prevalent form of dementia in the aging population; however, no effective therapy has been established. It has been previously demonstrated that daily intake of hydroxytyrosol (HT), a polyphenol in olive oil, at a daily dietary level mildly improves cognition in AD mice. In the present study, HT acetate (HT‐ac), which is a natural derivative of HT in olive oil that exhibits better bioactivity than HT improves cognition.Methods and ResultsHT‐ac to APP/PS1 is orally administered to transgenic mice and used Aβ‐treated neuronal cultures to explore the neuroprotective effects of HT‐ac in preventing AD progression. It is found that HT‐ac remarkably improved the escape latency, escape distance, and the number of platform crossings of AD mice in the water maze test by ameliorating neuronal apoptosis and decreasing inflammatory cytokine levels. It is further demonstrated that HT‐ac stimulated the transcription of ERβ and enhanced neuronal viability and electrophysiological activity in primary neurons but that these beneficial effects of HT‐ac are abolished upon ERβ deficiency.ConclusionsThis study suggests that as the bioactive component of olive oil, HT‐ac is a promising neuroprotective nutrient that may be used to alleviate AD‐related cognitive dysfunction.

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“…The APOE gene has 3 variants, called APOE2, APOE3, and APOE4, which are present at~7%, 79%, and~14%, respectively in the whole populace, and these show dissimilarities in lipid-as well as receptor-binding efficiency. The APOE allelic proteins vary by merely 1 or 2 amino acids including cysteine and arginine at residues 112 and 158, with APOE2 (cys112, cys158), APOE3 (cys112, arg158), and APOE4 (arg112, arg158) [61,62]. Although the APOE2 gene is associated with type III hyperlipoproteinemia, however, it has a defensive effect against AD.…”

Section: Apoe-polymorphism and Susceptibility Tomentioning

confidence: 99%

Molecular Insight into the Therapeutic Promise of TargetingAPOE4for Alzheimer’s Disease

Mamun

Uddin

Bashar

et al. 2020

Oxidative Medicine and Cellular Longevity

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes chronic cognitive dysfunction. Most of the AD cases are late onset, and the apolipoprotein E (APOE) isoform is a key genetic risk factor. The APOE gene has 3 key alleles in humans including APOE2, APOE3, and APOE4. Among them, APOE4 is the most potent genetic risk factor for late-onset AD (LOAD), while APOE2 has a defensive effect. Research data suggest that APOE4 leads to the pathogenesis of AD through various processes such as accelerated beta-amyloid aggregations that raised neurofibrillary tangle formation, cerebrovascular diseases, aggravated neuroinflammation, and synaptic loss. However, the precise mode of actions regarding in what way APOE4 leads to AD pathology remains unclear. Since APOE contributes to several pathological pathways of AD, targeting APOE4 might serve as a promising strategy for the development of novel drugs to combat AD. In this review, we focus on the recent studies about APOE4-targeted therapeutic strategies that have been advanced in animal models and are being prepared for use in humans for the management of AD.

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Estrogen Signaling in Alzheimer’s Disease: Molecular Insights and Therapeutic Targets for Alzheimer’s Dementia

Cited by 108 publications

References 177 publications

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

Hydroxytyrosol Acetate Improves the Cognitive Function of APP/PS1 Transgenic Mice in ERβ‐dependent Manner

Molecular Insight into the Therapeutic Promise of TargetingAPOE4for Alzheimer’s Disease

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