Estren prevents beta-amyloid-induced basal forebrain cholinergic loss and long-term spatial memory deficits in aged female mice

Basal forebrain cholinergic (BFC) deficits induced by amyloid beta (Aβ) are a well-established feature of Alzheimer’s disease (AD), and are linked to substantial cognitive decline. The gonadal steroid 17β-estradiol (E2) is neuroprotective; however, its therapeutic use is limited by adverse side effects. In contrast, activating non-classical E2 actions on intracellular signaling pathways offers therapeutic potential without invoking estrogenic off-target effects. Our previous studies demonstrated that after a highly toxic Aβ1–42 injection into the mouse basal forebrain, a single dose of 4-estren-3α, 17β-diol (estren), a selective activator of the non-classical estradiol pathway, prevented the loss of cholinergic signaling and also attenuated the Aβ1–42-induced learning deficits in young female mice. AD is an age-related disorder, and the most common cause of dementia in older adults. Therefore, in the current study, we examined the therapeutic potential of estren in aged (18-month-old) female mice. We found that estren prevented the Aβ1–42-induced loss of BFC neurons and the long-term spatial memory deficit following injection into the mouse basal forebrain of aged female mice. Notably, estren was more effective in reducing BFC cell death in aged mice following injection of Aβ1–42. The Aβ1–42 did not reduce the density of acetylcholine esterase-positive BFC projections in the somatosensory cortex of aged mice, as had been observed in young mice. Together, these findings suggest that selective activators of non-classical intracellular estrogen signaling when administered to older adults have the potential to reduce Aβ1–42-induced cholinergic neurodegeneration induced by increasing concentrations of Aβ and to preserve cognitive performance in AD.