Effects of Estrogen on Beta-Amyloid-Induced Cholinergic Cell Death in the Nucleus Basalis Magnocellularis

Abstract

Alzheimer disease is characterized by accumulation of β-amyloid (Aβ) and cognitive dysfunctions linked to early loss of cholinergic neurons. As estrogen-based hormone replacement therapy has beneficial effects on cognition of demented patients, and it may prevent memory impairments, we investigated the effect of estrogen-pretreatment on Aβ-induced cholinergic neurodegeneration in the nucleus basalis magnocellularis (NBM). We tested which Aβ species induces the more pronounced cholinotoxic effect in vivo. We injected different Aβ assemblies in the NBM of mice, and measured cholinergic cell and cortical fiber loss. Spherical Aβ oligomers had the most toxic effect. Pretreatment of ovariectomized mice with estrogen before Aβ injection decreased cholinergic neuron loss and partly prevented fiber degeneration. By using proteomics, we searched for proteins involved in estrogen-mediated protection and in Aβ toxicity 24 h following injection. The change in expression of, e.g., DJ-1, NADH ubiquinone oxidoreductase, ATP synthase, phosphatidylethanolamine-binding protein 1, protein phosphatase 2A and dimethylarginine dimethylaminohydrolase 1 support our hypothesis that Aβ induces mitochondrial dysfunction, decreases MAPK signaling, and increases NOS activation in NBM. On the other hand, altered expression of, e.g., MAP kinase kinase 1 and 2, protein phosphatase 1 and 2A by Aβ might increase MAPK suppression and NOS signaling in the cortical target area. Estrogen pretreatment reversed most of the changes in the proteome in both areas. Our experiments suggest that regulation of the MAPK pathway, mitochondrial pH and NO production may all contribute to Aβ toxicity, and their regulation can be prevented partly by estrogen pretreatment.

Dopamine-depletion and increased α-synuclein load induce degeneration of cortical cholinergic fibers in mice

“…Visualization of acetyl-cholinesterase (AChE) fibers was carried out according to the method of Hedreen et al [25], with slight modifications [26]. Adjacent series of sections were chosen from plates 31-40 [27].…”

“…The null hypothesis was rejected at the 0.05 p value level. AChE-positive fiber density in the layer V of the somatosensory and motor cortex was assessed in sections between bregma +0.62 and −0.10 mm [27] as described previously [29].…”

Estrogen receptor 1 PvuII and XbaI polymorphisms and susceptibility to Alzheimer’s disease: a meta-analysis

“…Estrogen induces synaptogenesis, acts as a neuroprotective agent, regulates neurotransmission in the central nervous system (CNS), and is associated with cognitive symptoms (Szego et al, 2011). Estrogen may inhibit the formation of the Ab protein and protect against Ab protein-induced neuronal death (Szego et al, 2011), however AD may be more prevalent in women, attributed in part, to estrogen (Bachman et al, 1992).…”

“…Estrogen may inhibit the formation of the Ab protein and protect against Ab protein-induced neuronal death (Szego et al, 2011), however AD may be more prevalent in women, attributed in part, to estrogen (Bachman et al, 1992). Thus estrogen is considered to play a role in the pathogenesis of AD (Xing et al, 2013).…”

Estrogen and Brain Protection

“…For example, Amyloid oligomer inhibited the activity of calcium/calmodulindependent protein kinase II and extracellular signal-regulated kinase in a manner ameliorated by estrogen treatment (Logan et al, 2011). In agreement with the protective effect of estrogen on protein kinase, Szego et al (2011) reported that the function of protein kinases correlated with avoidance learning behavior. In that study, the treatment with Amyloid oligomers impeded the learning in a manner that was protected by estrogen.…”