title: 17α-estradiol attenuates neuron loss in ovariectomized Dtg AβPP/PS1 mice.
abstract: Quantitative microanalysis of brains from patients with Alzheimer's disease (AD) find neuronal loss and neuroinflammation in structures that control cognitive function. Though historically difficult to recapitulate in experimental models, several groups have recently reported that by middle-age, transgenic mice that co-express high levels of two AD-associated mutations, amyloid-β protein precursor (AβPP(swe)) and presenilin 1 (PS1(ΔE9)), undergo significant AD-type neuron loss in sub-cortical nuclei with heavy catecholaminergic projections to the hippocampal formation. Here we report that by 13 months of age these dtg AβPP(swe)/PS1(ΔE9) mice also show significant loss of pyramidal neuron in a critical region for learning and memory, the CA1 subregion of hippocampus, as a direct function of amyloid-β (Aβ) aggregation. We used these mice to test whether 17α-estradiol (17αE2), a less feminizing and non-carcinogenic enantiomer of 17β-estradiol, protects against this CA1 neuron loss. Female dtg AβPP(swe)/PS1(ΔE9) mice were ovariectomized at 8-9 months of age and treated for 60 days with either 17αE2 or placebo via subcutaneous pellets. Computerized stereology revealed that 17αE2 ameliorated the loss of neurons in CA1 and reduced microglial activation in the hippocampus. These findings support the view that 17αE2, which may act through non-genomic mechanisms independent of traditional estrogen receptors, could prevent or delay the progression of AD in older men and women.
authors.affiliation: Department of Physiology & Biophysics, College of Medicine, Howard University, Washington, DC 20059, USA. kmanaye@howard.edu
authors.forename: Kebreten F
authors.initials: KF
authors.lastname: Manaye
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Allard
authors.forename: Sara
authors.initials: S
authors.lastname: Kalifa
authors.forename: Amy C
authors.initials: AC
authors.lastname: Drew
authors.forename: Guang
authors.initials: G
authors.lastname: Xu
authors.forename: Donald K
authors.initials: DK
authors.lastname: Ingram
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mouton
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010052:Ovariectomy; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D053764:Presenilin-1; D004958:Estradiol