Estrogen receptor-α is localized to neurofibrillary tangles in Alzheimer’s disease

Wang, Chunyu; Zhang, Fan; Jiang, Sirui; Siedlak, Sandra L.; Shen, Lu; Perry, George; Wang, Xinglong; Tang, Beisha; Zhu, Xiongwei

doi:10.1038/srep20352

Cited by 47 publications

(33 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, it is most likely that tau expression and/or pathology may affect SREBP‐2 signaling through transcriptional regulation. In this regard, we found that tau expression inhibited the transcription activity of estrogen receptor and its downstream signaling . Indeed, the mRNA levels of the SREBP‐2 target genes including SREBP‐2 and HMGcoAR are reduced in AD (Figure F).…”

Section: Discussionmentioning

confidence: 77%

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

et al. 2019

Self Cite

View full text Add to dashboard Cite

Disturbed neuronal cholesterol homeostasis has been observed in Alzheimer disease (AD) and contributes to the pathogenesis of AD. As the master switch of cholesterol biosynthesis, the sterol regulatory element-binding protein 2 (SREBP-2) translocates to the nucleus after cleavage/activation, but its expression and activation have not been studied in AD which is the focus of the current study. We found both a significant decrease in the nuclear translocation of N-terminal SREBP-2 accompanied by a significant accumulation of C-terminal SREBP-2 in NFT-containing pyramidal neurons in AD. N-terminal-SREBP-2 is also found in dystrophic neurites around plaques in AD brain. Western blot confirmed a significantly reduced nuclear translocation of mature SREBP-2 (mSREBP-2) in AD brain. Interestingly, reduced nuclear mSREBP-2 was only found in animal models of tauopathies such as 3XTg AD mice and P301L Tau Tg mice but not in CRND8 APP transgenic mice, suggesting that tau alterations likely are involved in the changes of mSREBP-2 distribution and activation in AD. Altogether, our study demonstrated disturbed SREBP-2 signaling in AD and related models, and proved for the first time that tau alterations contribute to disturbed cholesterol homeostasis in AD likely through modulation of nuclear mSREBP-2 translocation.

show abstract

Section: Discussionmentioning

confidence: 77%

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, our work could be used not only for future research where turns with an Xaa‐Pro cis conformation are required for modulation of the FKBP52 FK1 domain but also in the understanding of its link with hERα and Tau …”

Section: Discussionmentioning

confidence: 99%

Electronic circular dichroism and nuclear magnetic resonance studies of peptides derived from the FKBP52‐interacting β‐turn of the hERα ligand‐binding domain

et al. 2019

View full text Add to dashboard Cite

When located at the surface of proteins, turns containing a Pro‐Gly (PG) motif are often involved in protein/protein interactions and may participate in intracellular signaling cascades. As such, conformationally constrained short protein‐derived turn peptides offer promising perspectives for the development of drug candidates in the context of interfering with protein/protein interactions. From X‐ray crystal structures of the human estrogen receptor α ligand‐binding domain (hERα‐LBD), we have identified a short peptide motif (residues 363‐367, sequence: RVPGF) that adopts a type II β‐turn and which is a substrate of the FK1 peptidyl‐prolyl cis‐trans isomerase (PPIase or rotamase) catalytic site of the immunophilin FKBP52, when synthesized independently from the protein. Using ECD and NMR spectroscopy in combination with molecular dynamics simulations, we have embarked on a conformational study of peptides derived from this sequence, and we have explored the effects resulting from N‐ and C‐termini chemical modifications, cyclization, as well as from the replacement of both the proline and its preceding residue by various natural and non‐natural amino acids. All peptides are found to explore several conformational states in aqueous solution, differing by the conformation of the peptide bond preceding the proline residue of the central VPG segment. Trans isomers are characterized by a conformational equilibrium between a type II β‐turn around PG and an extended conformation, while cis isomers adopt a type VIb β‐turn centered on the Xaa‐Pro segment. We show here how limited chemical modifications can deeply influence the turn conformation of this FKBP52‐interacting peptide.

show abstract

“…E2 has a neuroprotective effect in several animal models of neurodegenerative diseases, such as ischemia, AD and experimental autoimmune encephalomyelitis (EAE; Arevalo et al, 2015 ). In addition, ERα interaction with neurofibrillary tangle and NGB-Aβ complexes suggest that proteins aggregates with ERα and NGB may inhibit their functions, therefore de-regulation impairs neuroprotective effect in AD (Sun et al, 2013 ; Seal et al, 2015 ; Wang et al, 2016 ). NGB is co-expressed with ERα in specific hypothalamic regions (Hundahl et al, 2008 ; Cutrupi et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

E2 Regulates Epigenetic Signature on Neuroglobin Enhancer-Promoter in Neuronal Cells

Guglielmotto

Reineri

Iannello

et al. 2016

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Estrogens are neuroprotective factors in several neurological diseases. Neuroglobin (NGB) is one of the estrogen target genes involved in neuroprotection, but little is known about its transcriptional regulation. Estrogen genomic pathway in gene expression regulation is mediated by estrogen receptors (ERα and ERβ) that bind to specific regulatory genomic regions. We focused our attention on 17β-estradiol (E2)-induced NGB expression in human differentiated neuronal cell lines (SK-N-BE and NT-2). Previously, using bioinformatics analysis we identified a putative enhancer in the first intron of NGB locus. Therefore, we observed that E2 increased the enrichment of the H3K4me3 epigenetic marks at the promoter and of the H3K4me1 and H3K27Ac at the intron enhancer. In these NGB regulatory regions, we found estrogen receptor alpha (ERα) binding suggesting that ERα may mediate chromatin remodeling to induce NGB expression upon E2 treatment. Altogether our data show that NGB expression is regulated by ERα binding on genomic regulatory regions supporting hormone therapy applications for the neuroprotection against neurodegenerative diseases.

show abstract

Estrogen receptor-α is localized to neurofibrillary tangles in Alzheimer’s disease

Cited by 47 publications

References 63 publications

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

Electronic circular dichroism and nuclear magnetic resonance studies of peptides derived from the FKBP52‐interacting β‐turn of the hERα ligand‐binding domain

E2 Regulates Epigenetic Signature on Neuroglobin Enhancer-Promoter in Neuronal Cells

Contact Info

Product

Resources

About