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bioRxiv · 10.1101/2024.07.22.604543

ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease

Demetriou, A.·Lindqvist, B.·Ali, H. G.·Shamekh, M. M.·Maioli, S.·Inzunza, J.·Varshney, M.·Nalvarte, I.
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Abstract

Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimers disease (AD). Activation of estrogen receptor beta (ER{beta}) can be clinically relevant since it avoids the negative systemic effects of ER activation. However, very few studies have explored ER{beta}-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ER{beta} in mediating sex-specific protection against AD pathology in the clinically relevant AppNL-G-F knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and female AppNL-G-F mice with the selective ER{beta} agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ER{beta}-knockout mice were used to assess ER{beta}s effect on microglial activation and phagocytosis. We find that ER{beta} activation protects against amyloid pathology and cognitive decline in male and female AppNL-G-F mice. Ovariectomy increased soluble amyloid beta (A{beta}) in cortex and insoluble A{beta} in hippocampus, but had otherwise limited effects on pathology. We further identify that ER{beta} does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ER{beta} protects against AD pathology differently in males and females, warranting reassessment of ER{beta} in combating AD.

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Demetriou, A., Lindqvist, B., Ali, H. G., Shamekh, M. M., Maioli, S., Inzunza, J., Varshney, M., Nalvarte, I.. 2024-07-23. ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease. https://doi.org/10.1101/2024.07.22.604543

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