Abstract
AbstractBackgroundC/EBPb/AEP pathway are escalated in the brain in an age‐dependent manner and proteolytically cleaves APP and Tau and a‐Synuclein, facilitating AD and PD pathologies.MethodC/EBPb/AEP pathway couples different risk factors that elicit inflammation to Alzheimer’s disease. To explore why women are more vulnerable for AD, we investigated different hormones altered during menopause and found FSH (follicle‐stimulating hormone) strongly activated this signalling, leading to AD pathogenesis in different mouse models. Employing immuno‐EM and knockout tissues, we demonstrated that FSHR is expressed in mouse and human brain neurons. Notably, FSH administration drives AD onset in young male and female mice, whereas anti‐FSH robustly diminishes AD progression in overiactomized female 3xTg mice. Moreover, deletion of FSHR or C/EBPb from the neurons of 3xTg mice attenuates AD pathologies.ResultElevated FSH during menopause activates C/EBPb/AEP signalling, which subsequently cleaves both APP and Tau, triggering AD onset. Blockade of FSH abrogates overiactomy‐induced AD pathologies and restores the cognitive dysfunctions in AD mouse models.ConclusionFSH elevation after menopause elicits women susceptibility to AD via activating C/EBPb/AEP pathway. Inhibition of FSH/FSHR may provide an innovative therapeutic strategy for treating AD.
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