Treatment of beta amyloid 1–42 (Aβ1–42)-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo

• Published in: Scientific reports Vol. 6; no. 1; p. 21101
• Main Authors: Kwakowsky, Andrea, Potapov, Kyoko, Kim, SooHyun, Peppercorn, Katie, Tate, Warren P., Ábrahám, István M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-02-2016; Nature Publishing Group
• Subjects: 13; 13/51; 14; 14/1; 14/19; 17β-Estradiol; 631/378; 631/378/1689/1283; 64; 64/60; 692/163; 96; 96/95; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Animals; Basal forebrain; Basal Forebrain - drug effects; Basal Forebrain - metabolism; Basal Forebrain - pathology; Cell Count; Cholinergic Fibers - drug effects; Cholinergic Fibers - metabolism; Cholinergic Fibers - pathology; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; Cholinergic Neurons - pathology; Cognitive ability; Cortex; Estrogen Receptor alpha - metabolism; Estrogens; Estrogens - metabolism; Estrogens - pharmacology; Female; Fibers; Forebrain; Humanities and Social Sciences; Injection; Innervation; Intracellular; Intracellular signalling; Learning - drug effects; Mice; Mice, Knockout; multidisciplinary; Neurodegenerative diseases; Neurons; Neuroprotection; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Phosphorylation; Rodents; Science; Side effects; Signal transduction; Signal Transduction - drug effects; Somatosensory Cortex - drug effects; Somatosensory Cortex - metabolism; Somatosensory Cortex - pathology; Xenoestrogens; β-Amyloid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep21101

In Alzheimer’s disease (AD), there is a loss in cholinergic innervation targets of basal forebrain which has been implicated in substantial cognitive decline. Amyloid beta peptide (Aβ
1–42
) accumulates in AD that is highly toxic for basal forebrain cholinergic (BFC) neurons. Although the gonadal steroid estradiol is neuroprotective, the administration is associated with risk of off-target effects. Previous findings suggested that non-classical estradiol action on intracellular signaling pathways has ameliorative potential without estrogenic side effects. After Aβ
1–42
injection into mouse basal forebrain, a single dose of 4-estren-3α, 17β-diol (estren), the non-classical estradiol pathway activator, restored loss of cholinergic cortical projections and also attenuated the Aβ
1–42
-induced learning deficits. Estren rapidly and directly phosphorylates c-AMP-response–element-binding-protein and extracellular-signal-regulated-kinase-1/2 in BFC neurons and restores the cholinergic fibers via estrogen receptor-α. These findings indicated that selective activation of non-classical intracellular estrogen signaling has a potential to treat the damage of cholinergic neurons in AD.