Estrogen Lowers Alzheimer β-Amyloid Generation by Stimulating trans-Golgi Network Vesicle Biogenesis

Abstract

Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, ␤-amyloid (A␤) burden in animal models of Alzheimer's disease, and secretion of A␤ from neuronal cultures. The biological basis for these effects remains unknown. Here, utilizing cell-free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17␤-estradiol (17␤-E2) stimulates formation of vesicles containing the ␤-amyloid precursor protein (␤APP) from the transGolgi network (TGN). Accelerated ␤APP trafficking precludes maximal A␤ generation within the TGN. 17␤-E2 appears to modulate TGN phospholipid levels, particularly those of phosphatidylinositol, and to recruit soluble trafficking factors, such as Rab11, to the TGN. Together, these results suggest that estrogen may exert its anti-A␤ effects by regulating ␤APP trafficking within the late secretory pathway. These results suggest a novel mechanism through which 17␤-E2 may act in estrogen-responsive tissues and illustrate how altering the kinetics of the transport of a protein can influence its metabolic fate.Reports that post-menopausal estrogen replacement therapy (ERT) 1 is clinically efficacious in delaying the onset of Alzheimer's disease (AD) (1) or improving cognition (2) in post-menopausal women have been corroborated by numerous studies (3-5). Reports questioning the validity of these retrospective studies (6) demonstrated that women with clinically defined AD have no improvement on specific cognitive tasks following short (2-15-month) trials of estrogen treatment. However, the neuroprotective effects of estrogen are hypothesized to safeguard against the development of AD and not to aid in recovering lost function. The biological mechanism(s) through which estrogen exerts its neuroprotective effects remain largely unknown; hypotheses have included modulation of basal forebrain cholinergic activity, dendritic plasticity, N-methyl-D-aspartic acid (NMDA) receptor density, and regulation of neurotrophin signaling pathways (7).ERT may slow AD progression by reducing the release of A␤, the primary constituent of amyloid plaques, into brain parenchyma. This phenomenon was first described in non-neuronal (8) and neuronal (9) cell culture. It has now received support from animal models demonstrating that ovariectomized guinea pigs (10) and transgenic mutant ␤APP/PS1-expressing mice (11) develop increased levels of parenchymal A␤ compared with intact littermates. This A␤ burden is reversible with postsurgical estrogen replacement. In addition, a recent study (12) demonstrates an inverse relationship between the levels of 17␤-E2 and A␤42, the more amyloidogenic A␤ variant, in the cerebrospinal fluid of female patients with AD. In summary, results from retrospective clinical trials, recent and on-going animal studies, and corroborating cell culture data all support the hypothesis that post-menopausal cessation of estrogen production may facilitate A␤ deposition and that the clinical efficacy of ERT may be due, in part, to a direct A␤-lowering effect.A␤ is p...

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

“…Although the neuroprotective properties of beta-estradiol [51] have been already reported in different diseases and models [52,53], and estrogen effects on neuronal viability have been demonstrated both in vitro and in in vivo [54,55], the underlying molecular mechanisms are still elusive. Our data indicate that beta-estradiol treatment is neuroprotective since it results in increased cell survival and proliferation, accompanied by reduction of ubiquitinated protein inclusions.…”

Liquiritigenin inhibits Aβ25–35-induced neurotoxicity and secretion of Aβ1–40 in rat hippocampal neurons

“…It has outstanding neuroprotective and neurotrophic activities and has been linked to neurodegenerative diseases, including Alzheimer's disease (AD) [1,2] . A large body of work has shown that estrogen can block β-amyloid peptide (Aβ)-induced neuronal cell death and influence Aβ secretion [3][4][5][6][7] . However, long-term compliance with estrogen administration is estimated to be no more than 15%-40% because of undesirable side effects [8][9][10] .…”

“…Liquiritigenin (7,4'-dihydroxyflavanone, Figure 1) is a flavonoid extracted from Glycyrrhizae radix that exhibits lifeenhancing properties and is frequently used in traditional Oriental medicine to treat injury or swelling and for detoxification. Our interest in liquiritigenin developed as a result of the following observations.…”

Estrogen and Brain Protection

“…Several studies support this notion that estrogen treatment profoundly decreased the levels of amyloid precursor protein by enhancing the degradation of this precursor through the -and -secretase pathways (Amtul et al, 2010). Alternatively, estrogen may reduce available amyloid precursor protein by stimulating the formation of vesicles that uptake this precursor-protein, thereby precluding maximal generation of Amyloid (Greenfield et al, 2002). These findings suggest another mechanism underlying estrogen's protection against Alzheimer's disease involving Amyloid degredation (Liang et al, 2010).…”

“…In diverse animal models of Alzheimer's disease, estrogen has prevented or delayed the development of Alzheimer's disease pathology in particular Amyloid accumulation and plaque formation (Carroll et al, 2007;Zheng et al, 2002). Mechanistically, estrogen may regulate the production of Amyloid and in turn, sustain an improved Amyloid homeostasis by increasing the metabolism of amyloid precursor protein and destabilization of Amyloid fibrils (Greenfield et al, 2002;Morinaga et al, 2007). Estrogen's bioenergetic protection may also influence Alzheimer's disease.…”