Non-nuclear Estrogen Receptor Signaling as a Promising Therapeutic Target to Reverse Alzheimer's Disease-related...

Although Alzheimer's disease (AD) affects millions of individuals worldwide, there are currently no effective treatments available. Recent findings have suggested that non-nuclear estrogen receptor (ER) signaling represents promising therapeutic target for central nervous system disorders, offering potential treatments without the significant side effects associated with the activation of nuclear ERs. Because ER signaling deficiency and autophagy impairment have been linked to AD etiology, the present study aimed to selectively target non-nuclear ERs signaling pathways with PaPE-1 and identify autophagy-related mechanisms of neuroprotection in a cellular model of AD. The present study demonstrated that PaPE-1 protected mouse cortical neurons from AD pathology, as evidenced by MAP2-specific labeling. Posttreatment with PaPE-1 reversed the amyloid-β (Aβ)-evoked decrease in autophagic vesicles level, and increased the expression of autophagy-related mRNAs and proteins, accompanied by hypomethylation of the Atg7 gene. Moreover, posttreatment with PaPE-1 increased the levels of membrane fraction receptors ESR1/ERα and ESR2/ERβ, which corresponds to increased Esr1 and Esr2 mRNA expression and DNA hypomethylation of specific genes. In addition to inhibiting DNA methylation of autophagy and ER-related genes, PaPE-1 did not alter global DNA methylation but stimulated HAT activity in Aβ-treated cells. In summary, PaPE-1 promoted neuroprotection against Aβ-induced toxicity that involved stimulation of autophagy, upregulation of membrane ESR1 and ESR2 and decreased DNA methylation of respective genes. The present study proposes a novel therapeutic approach against AD that is based on the selective activation of non-nuclear ER signaling to overcome Aβ-induced autophagy deficits and normalize the epigenetic status of cerebral neurons.