Both estrogen and raloxifene protect against β-amyloid-induced neurotoxicity in estrogen receptor α-transfected PC12 cells by activation of telomerase activity via Akt cascade

Abstract

Although estrogen is known to protect against -amyloid (A )-induced neurotoxicity, the mechanisms responsible for this effect are only beginning to be elucidated. In addition, the effect of raloxifene on A -induced neurotoxicity remains unknown. Here we investigated whether raloxifene exhibits similar neuro-protective effects to estrogen against A -induced neurotoxicity and the mechanism of the effects of these agents in PC12 cells transfected with the full-length human estrogen receptor (ER) gene (PCER). Raloxifene, like 17 -estradiol (E 2 ), significantly inhibited A -induced apoptosis in PCER cells, but not in a control line of cells transfected with vector DNA alone (PCCON). Since telomerase activity, the level of which is modulated by regulation of telomerase catalytic subunit (TERT) at both the transcriptional and posttranscriptional levels, is known to be involved in suppressing apoptosis in neurons, we examined the effect of E 2 and raloxifene on telomerase activity. Although both E 2 and raloxifene induced telomerase activity in PCER cells, but not in PCCON cells, treated with A , they had no effect on the level of TERT expression. These results suggest that neither E 2 nor raloxifene affects the telomerase activity at the transcriptional level. We therefore studied the mechanism by which E 2 and raloxifene induce the telomerase activity at the post-transcriptional level. Both E 2 and raloxifene induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase inhibitor, LY294002, attenuated both E 2 -and raloxifene-induced activation of the telomerase activity. Moreover, both E 2 and raloxifene induced both the phosphorylation of TERT at a putative Akt phosphorylation site and the association of nuclear factor B with TERT. Our findings suggest that E 2 and raloxifene exert neuroprotective effects by telomerase activation via a post-transcriptional cascade in an experimental model relevant to Alzheimer's disease.

Beta-amyloid toxicity and reversal in embryonic rat septal neurons

“…These may be more effective than NGF itself. Estrogen is protective against Aβ in cell lines such as PC12 and human neuronal cells [4,10] but was ineffective on the differentiated cells in this study. The estrogen and NGF may be acting by a similar pathway as both alter phosphotyrosine content in septal neurons over a similar time period [14].…”

Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

“…Collectively, these effects could explain the reported protective actions of estrogen in AD. It should be mention that the SERM, raloxifene has also been shown to protect against β-amyloid-induced cell death [199], and it has been reported to decrease risk of AD and cognitive impairment in postmenopausal women [206]. As a whole, the above studies support a potential protective role for estrogen in AD, which deserves further study.…”

“…However, a number of studies have shown that estrogen can protect neurons against β-amyloid toxicity [73,185,[195][196][197][198][199], oxidative stress [110][111][112][113]195,200] and excitotoxicity [67,195,201,202], events suggested to participate in the pathology of AD. Additionally, estrogen has been shown to induce dephosphorylation of the tau protein and prevent its hyperphosphorylation in neurons [203].…”

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

“…Phosphorylation of Akt leads to its activation and protects cells against genomic DNA degradation and membrane PS exposure [45,61,105]. Up-regulation of Akt activity during multiple injury paradigms, such as vascular and cardiomyocyte ischemia [106,107], free radical exposure [45,108], N-methyl-D-aspartate toxicity [109], hypoxia [110,111], β-amyloid toxicity [112][113][114], DNA damage [31, 41,110,115], metabotropic receptor signaling [38,116,117], cell metabolic pathways [42,63], and oxidative stress [31,33,41] increases cell survival. Cytoprotection through Akt also can involve control of inflammatory cell activation [33, 41,61], transcription factor regulation [118], maintenance of mitochondrial membrane potential (ΔΨ m ), prevention of cytochrome c release [45,61,105], and blockade of caspase activity [45,61,110] In addition to targeting the activity of membrane PS exposure and microglial activation, nicotinamide inhibits several pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, interleukin-8, tissue factor, and tumor necrosis factor-α (TNF-α) [119][120][121][122].…”