Increased ERb expression during ageing could be neuroprotective against Alzheimer’s disease development in the male but not the female brain

Background Age is the biggest risk factor for Alzheimer’s disease (AD) with cases doubling every 5 years after 65 years. Increased risk is also associated with being female. This gender difference in AD incidence could be partly explained by menopause‐related hormone deficiencies during ageing. Clin...

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Bibliographic Details
Published in:Alzheimer's & dementia 2021-12, Vol.17, p.e052991-n/a
Main Authors: Almutairi, Jawza A, Gee, Julia M, Kidd, Emma J
Format: Article
Language:English
Online Access:Get full text
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Summary:Background Age is the biggest risk factor for Alzheimer’s disease (AD) with cases doubling every 5 years after 65 years. Increased risk is also associated with being female. This gender difference in AD incidence could be partly explained by menopause‐related hormone deficiencies during ageing. Clinical studies concluded that the age when hormone replacement therapy was started, especially after the menopause, was critical in delaying AD development. Deposition of b‐amyloid (Ab) in the hippocampus and cortex is the key pathological feature in AD. Much evidence has demonstrated that oestrogen activation of oestrogen receptors (ER) in neurones decreases Ab accumulation and antagonizes its cytotoxic effects in AD. ERb is an ER subtype highly expressed in the nervous system. In vivo studies reported that ERb activation reduces the cytotoxic effect of Ab through the Akt pathway and improves learning and memory capacity in AD models. However, this finding has not yet been investigated in the clinic. We hypothesised that the increased risk of AD in women could be partly explained by alterations in the levels of oestrogen, its receptors and downstream signalling pathways in the female brain during ageing affecting the expression of AD biomarkers. Method Levels of ERb, phosphorylated and total Akt, APP, its secretases and metabolites were measured using immunoblotting and ELISA in frontal cortical brain samples from young (20‐30), middle‐aged (45‐55) and old (70‐90) men and women with no history of dementia. Result In female brains significant age‐related increases in APP and the secretases were observed but were not seen in male samples. bCTF and the Aβ42:40 ratio also showed age‐related increases only in women. Aβ42 levels were higher in elderly female samples compared to male. In contrast, significant age‐related increases in ERb and pAkt:total Akt were only seen in male samples. Conclusion We demonstrate for the first time a sex difference in the expression of AD biomarkers with ageing with a novel age‐related increase in APP in the ageing female brain. The increase in ERb expression in male but not female samples could result in a neuroprotective effect against Aβ cytotoxicity. Our findings could partly explain female vulnerability for AD development.
ISSN:1552-5260
1552-5279
DOI:10.1002/alz.052991