Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease

Abstract

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.

Keywords: Alzheimer’s disease; basal forebrain cholinergic neurons 4; estradiol 1; neurotrophin receptors 3; neurotrophins 2.

Figure 1

(A) Estrogen receptor structure and function. Homology between ERα and ERβ: amino acid identity (%) in the N-terminal activation function 1 region (AF-1), DNA-binding domain (DBD), hinge region (H), ligand-binding domain (LBD), and C-terminal function 2 domain (AF-2); (B) interaction of neurotrophin receptor and estrogen signaling pathways. Schematic outlining of the neurotrophin receptors and their associated peptides and a simplified diagram describing the main signaling pathways activated by the Trk and p75 receptors. Activation and subsequent phosphorylation of the Trk receptor results in the activation of the MEK/ERK signaling pathway, that leads to phosphorylation of transcription factors (TFs) like CREB and promotes cell differentiation and survival; and the PI3K/Akt pathway that promotes cell survival. The p75NTR signals modulate the NF-κB and JNK pathways, which promotes inflammation and cell survival or apoptosis respectively. The classical and non-classical estrogen pathway interacts with neurotrophin system and regulates neuronal survival and ameliorative effects on the BFCN. Dashed arrows indicate various targets.