Selection of novel activators of non-genomic estrogen-like signaling (ANGELS) with promising potential for Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia, affecting elderly women two- to threefold more than similar aged man, or the younger generations. Although 17β-estradiol offers neuroprotection, its clinical use is limited by serious side effects. This study explored a molecular group called ANGELS (Activators of Non-Genomic Estrogen-Like Signaling) as safer alternatives. A steroid library was screened via computational docking to estrogen receptor α. The top binders were preselected via in vitro and in vivo tests. The neuroprotective effect was examined in two mouse models of AD (neurotoxic and genetic). Morphological and behavioral changes were investigated. From the 15 top binders six molecules were identified without estrogen-like uterus effects and with rapid kinase activation. The chosen compound (A3270), acutely given, significantly restored cholinergic fiber loss without affecting cell loss or AD-related morphologies (amyloid β and phospho-Tau). Furthermore, it increased locomotor activity but had no effect on short term memory. These molecules lack ERE reporter activity and uterotrophic effects in vitro and in vivo and A3270 was promising in two AD model mice. We believe that these or similar compounds may provide novel approaches for AD therapy.