Levels of Estrogen Receptors α and β in Frontal Cortex of Patients with Alzheimers Disease: Relationship to Mini-Mental State Examination Scores

Abstract

Estrogen exerts beneficial effects on the brain throughout life. Studies demonstrate that estrogen is neuroprotective and that reduced brain estrogen activity may influence the clinical course of Alzheimer's disease (AD). Changes in levels of estrogen receptors have been detected in postmortem brain tissue of AD patients. Very little is known about the relationship between clinical stage and levels of estrogen receptors in postmortem brain. We hypothesized that estrogen receptor levels would be related to severity of cognitive impairment assessed proximate to death. Western blotting was used to quantify ER-alpha and ER-beta in nuclear, cytosolic, and crude membrane fractions of superior frontal cortex from 25 AD patients. Multiple linear regression analyses adjusted for age, sex, and education showed a significant linear relationship between Mini-Mental State Examination score (MMSE) and wild-type nuclear ER-alpha (â = 5.463, p = 0.03), but none between MMSE and wild-type nuclear ER-beta (â = 2.29, p = 0.36). We incidentally observed additional higher and lower molecular mass bands for ER-alpha in study subjects. Additional experiments performed on frontal cortex nuclear fractions prepared from subjects enrolled in a different study confirmed that these same bands are present in female and males with and without AD. Together our data show a relationship between wild-type ER-alpha and level of cognitive impairment in AD, and also suggest the possibility that variant isoforms of ER-alpha may be present in frontal cortex of patients with and without AD.

The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimers Disease

“…Specifically, an ER shift from the nucleus to the cytoplasm has been observed in both human cases [115] and AD transgenic mice [116]. Further, various clinical studies have reported that cortical ER levels correlate with mini-mental state examination scores in AD women [117] and that certain ER allele differences correlate with higher AD risk in women with Down syndrome [118]. Even hippocampal ER immunoreactivity in AD is reportedly increased compared to age-matched controls [119].…”

Estrogen: A master regulator of bioenergetic systems in the brain and body

“…ERα also becomes less sensitive to E 2 treatment as animals age; this is in contrast to ERβ, which shows decreased levels with age but remains responsive to E 2 treatment (Waters et al, 2011). Clinical studies have shown a linear relationship between Mini Mental State Exam (MMSE) score and ERα β, in the frontal cortex of Alzheimer’s patients (Kelly et al, 2008). The existence of variant isoforms of ERα that may influence cognitive impairment has been proposed (Kelly et al, 2008); this was later observed in a cohort of non-demented elderly (Yaffe et al, 2009).…”

“…Clinical studies have shown a linear relationship between Mini Mental State Exam (MMSE) score and ERα β, in the frontal cortex of Alzheimer’s patients (Kelly et al, 2008). The existence of variant isoforms of ERα that may influence cognitive impairment has been proposed (Kelly et al, 2008); this was later observed in a cohort of non-demented elderly (Yaffe et al, 2009). Thus the data show that decreased ERα responsiveness may mediate cognitive impairment and dementia; during aging, although ERβ remains responsive to E 2 , it is unable to compensate for the loss of ERα.…”

New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection

“…The detected levels of ERs in postmortem brain tissue of AD patients is related to the severity of cognitive impairment assessed proximate to death, and only the reduction of ER-α from frontal cortex is correlated to Mini-Mental State Examination score, not the ER-β [95]. The spectrometry, immunohistochemistry, and quantitative real-time PCR of the autopsied Japanese AD patients compared to controls [96] have revealed a glial nuclear ER-β expression significantly lower in white matter in the AD group vs. controls, without any significant differences in estrogen concentrations, and the conclusion was that estrogens have effects on glias and neurons in the etiology of AD, and the correlation between BMI and estrogen concentrations in the frontal lobe suggests the importance of non-brain sources of estrogens particularly in controls.…”

“…Regarding ERs, there are new details about the genes, and mRNA variants of ER-α expressed in different parts of the human brain, and there are specific ER-α mRNA splice variants or isoforms of ER-α in the medial mammillary nucleus (MMN) in AD [102] or in the frontal cortex in AD patients [95], and their relationship to cognitive impairment.…”