PNU282987 inhibits amyloid‑β aggregation by upregulating astrocytic endogenous αB‑crystallin and HSP‑70 via regulation of the α7AChR, PI3K/Akt/HSF‑1 signaling axis

Ren,Zhenkui; Dong,Zhihui; Xie,Peng; Lv,Ju; Hu,Yumei; Guan,Zhizhong; Zhang,Chunlin; Yu,Wenfeng

doi:10.3892/mmr.2020.11132

PNU282987 inhibits amyloid‑β aggregation by upregulating astrocytic endogenous αB‑crystallin and HSP‑70 via regulation of the α7AChR, PI3K/Akt/HSF‑1 signaling axis

Authors:
- Zhenkui Ren
- Zhihui Dong
- Peng Xie
- Ju Lv
- Yumei Hu
- Zhizhong Guan
- Chunlin Zhang
- Wenfeng Yu
View Affiliations

Affiliations: Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, College of Basic Medical Sciences, Guiyang, Guizhou 550004, P.R. China, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China
Published online on: May 5, 2020 https://doi.org/10.3892/mmr.2020.11132
Pages: 201-208
Copyright: © Ren et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder. Abnormal aggregation of the neurotoxic amyloid‑β (Aβ) peptide is an early event in AD. The activation of astrocytic α7 nicotinic acetylcholine receptor (α7 nAChR) can inhibit Aβ aggregation; thus, the molecular mechanism between α7 nAChR activation and Aβ aggregation warrants further investigation. In the present study, Aβ oligomer levels were assessed in astrocytic cell lysates after treatment with PNU282987 (a potent agonist of α7 nAChRs) or co‑treatment with LY294002, a p‑Akt inhibitor. The levels of heat shock factor‑1 (HSF‑1), heat shock protein 70 (HSP‑70), and αB‑crystallin (Cryab) in astrocytes treated with PNU282987 at various time‑points or co‑treated with methyllycaconitine (MLA), a selective α7 nAChR antagonist, as well as co‑incubated with LY294002 were determined by western blotting. HSP‑70 and Cryab levels were determined after HSF‑1 knockdown (KD) in astrocytes. PNU282987 markedly inhibited Aβ aggregation and upregulated HSF‑1, Cryab, and HSP‑70 in primary astrocytes, while the PNU282987‑mediated neuroprotective effect was reversed by pre‑treatment with MLA or LY294002. Moreover, the HSF‑1 KD in astrocytes effectively decreased Cryab, but not HSP‑70 expression. HSF‑1 is necessary for the upregulation of Cryab expression, but not for that of HSP‑70. HSF‑1 and HSP‑70 have a neuroprotective effect. Furthermore, the neuroprotective effect of PNU282987 against Aβ aggregation was mediated by the canonical PI3K/Akt signaling pathway activation.

View Figures

View References

1	Schilling LP, Pascoal TA, Zimmer ER, Mathotaarachchi S, Shin M, de Mello Rieder CR, Gauthier S, Palmini A and Rosa-Neto P; Alzheimer's Disease Neuroimaging Initiative, : Regional Amyloid-β load and white matter abnormalities contribute to hypometabolism in Alzheimer's dementia. Mol Neurobiol. 56:4916–4924. 2019. View Article : Google Scholar : PubMed/NCBI
2	Karran E, Mercken M and De Strooper B: The amyloid cascade hypothesis for Alzheimer's disease: An appraisal for the development of therapeutics. Nat Rev Drug Discov. 10:698–712. 2011. View Article : Google Scholar : PubMed/NCBI
3	Glabe CG and Kayed R: Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. Neurology. 66 (2 Suppl 1):S74–S78. 2006. View Article : Google Scholar : PubMed/NCBI
4	Saito T, Hisahara S, Iwahara N, Emoto MC, Yokokawa K, Suzuki H, Manabe T, Matsumura A, Suzuki S, Matsushita T, et al: Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease. Free Radic Biol Med. 145:20–32. 2019. View Article : Google Scholar : PubMed/NCBI
5	Sidoryk-Wegrzynowicz M, Wegrzynowicz M, Lee E, Bowman AB and Aschner M: Role of astrocytes in brain function and disease. Toxicol Pathol. 39:115–123. 2011. View Article : Google Scholar : PubMed/NCBI
6	Alberini CM, Cruz E, Descalzi G, Bessieres B and Gao V: Astrocyte glycogen and lactate: New insights into learning and memory mechanisms. Glia. 66:1244–1262. 2018. View Article : Google Scholar : PubMed/NCBI
7	Steinman MQ, Gao V and Alberini CM: The role of lactate-mediated metabolic coupling between astrocytes and neurons in long-term memory formation. Front Integr Neurosci. 10:102016. View Article : Google Scholar : PubMed/NCBI
8	Nielsen HM, Veerhuis R, Holmqvist B and Janciauskiene S: Binding and uptake of A beta1-42 by primary human astrocytes in vitro. Glia. 57:978–988. 2009. View Article : Google Scholar : PubMed/NCBI
9	Pihlaja R, Koistinaho J, Malm T, Sikkilä H, Vainio S and Koistinaho M: Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer's disease. Glia. 56:154–163. 2008. View Article : Google Scholar : PubMed/NCBI
10	Jabbari Azad F, Talaei A, Rafatpanah H, Yousefzadeh H, Jafari R, Talaei A and Farid Hosseini R: Association between Cytokine production and disease severity in Alzheimer's disease. Iran J Allergy Asthma Immunol. 13:433–439. 2014.PubMed/NCBI
11	Hoskin JL, Al-Hasan Y and Sabbagh MN: Nicotinic acetylcholine receptor agonists for the treatment of Alzheimer's dementia: An update. Nicotine Tob Res. 21:370–376. 2019. View Article : Google Scholar : PubMed/NCBI
12	Broide RS, Winzer-Serhan UH, Chen Y and Leslie FM: Distribution of α7 nicotinic acetylcholine receptor subunit mRNA in the developing mouse. Front Neuroanat. 13:762019. View Article : Google Scholar : PubMed/NCBI
13	Parri HR, Hernandez CM and Dineley KT: Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease. Biochem Pharmacol. 82:931–942. 2011. View Article : Google Scholar : PubMed/NCBI
14	Yu WF, Guan ZZ, Bogdanovic N and Nordberg A: High selective expression of alpha7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer's disease and patients carrying Swedish APP 670/671 mutation: A possible association with neuritic plaques. Exp Neurol. 192:215–225. 2005. View Article : Google Scholar : PubMed/NCBI
15	Yu W, Mechawar N, Krantic S, Chabot JG and Quirion R: Upregulation of astrocytic α7 nicotinic receptors in Alzheimer's disease brain-possible relevant to amyloid pathology. Mol Neurodegener. 7 (Suppl 1):O72012. View Article : Google Scholar
16	Shammas SL, Waudby CA, Wang S, Buell AK, Knowles TP, Ecroyd H, Welland ME, Carver JA, Dobson CM and Meehan S: Binding of the molecular chaperone αB-crystallin to Aβ amyloid fibrils inhibits fibril elongation. Biophys J. 101:1681–1689. 2011. View Article : Google Scholar : PubMed/NCBI
17	Wilhelmus MM, Boelens WC, Otte-Höller I, Kamps B, de Waal RM and Verbeek MM: Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity. Brain Res. 1089:67–78. 2006. View Article : Google Scholar : PubMed/NCBI
18	Raman B, Ban T, Sakai M, Pasta SY, Ramakrishna T, Naiki H, Goto Y and Rao ChM: AlphaB-crystallin, a small heat-shock protein, prevents the amyloid fibril growth of an amyloid beta-peptide and beta2-microglobulin. Biochem J. 392:573–581. 2005. View Article : Google Scholar : PubMed/NCBI
19	Volovik Y, Moll L, Marques FC, Maman M, Bejerano-Sagie M and Cohen E: Differential regulation of the heat shock factor 1 and DAF-16 by neuronal nhl-1 in the nematode C. elegans. Cell Rep. 9:2192–2205. 2014. View Article : Google Scholar : PubMed/NCBI
20	McCarthy KD and de Vellis J: Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 85:890–902. 1980. View Article : Google Scholar : PubMed/NCBI
21	Klein WL: Abeta toxicity in Alzheimer's disease: Globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int. 41:345–352. 2002. View Article : Google Scholar : PubMed/NCBI
22	Rönicke R, Mikhaylova M, Rönicke S, Meinhardt J, Schröder UH, Fändrich M, Reiser G, Kreutz MR and Reymann KG: Early neuronal dysfunction by amyloid β oligomers depends on activation of NR2B-containing NMDA receptors. Neurobiol Aging. 32:2219–2228. 2011. View Article : Google Scholar : PubMed/NCBI
23	Kihara T, Shimohama S, Urushitani M, Sawada H, Kimura J, Kume T, Maeda T and Akaike A: Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res. 792:331–334. 1998. View Article : Google Scholar : PubMed/NCBI
24	Steiner RC, Heath CJ and Picciotto MR: Nicotine-induced phosphorylation of ERK in mouse primary cortical neurons: Evidence for involvement of glutamatergic signaling and CaMKII. J Neurochem. 103:666–678. 2007. View Article : Google Scholar : PubMed/NCBI
25	Valle-Casuso JC, Gonzalez-Sanchez A, Medina JM and Tabernero A: HIF-1 and c-Src mediate increased glucose uptake induced by endothelin-1 and connexin43 in astrocytes. PLoS One. 7:e324482012. View Article : Google Scholar : PubMed/NCBI
26	Herrero-González S, Valle-Casuso JC, Sánchez-Alvarez R, Giaume C, Medina JM and Tabernero A: Connexin43 is involved in the effect of endothelin-1 on astrocyte proliferation and glucose uptake. Glia. 57:222–233. 2009. View Article : Google Scholar : PubMed/NCBI
27	Yang T, Xiao T, Sun Q and Wang K: The current agonists and positive allosteric modulators of α7 nAChR for CNS indications in clinical trials. Acta Pharm Sin B. 7:611–622. 2017. View Article : Google Scholar : PubMed/NCBI
28	Kalkman HO and Feuerbach D: Modulatory effects of α7 nAChRs on the immune system and its relevance for CNS disorders. Cell Mol Life Sci. 73:2511–2530. 2016. View Article : Google Scholar : PubMed/NCBI
29	Chen T, Wang Y, Zhang T, Zhang B and Chen L, Zhao L and Chen L: Simvastatin Enhances activity and trafficking of α7 nicotinic acetylcholine receptor in hippocampal neurons through PKC and CaMKII signaling pathways. Front Pharmacol. 9:3622018. View Article : Google Scholar : PubMed/NCBI
30	Mannelli LDC, Tenci B, Zanardelli M, Failli P and Ghelardini C: α7 nicotinic receptor promotes the neuroprotective functions of astrocytes against oxaliplatin neurotoxicity. Neural Plasticity. 2015:1–10. 2015. View Article : Google Scholar
31	Hardy JA and Higgins GA: Alzheimer's disease: The amyloid cascade hypothesis. Science. 256:184–185. 1992. View Article : Google Scholar : PubMed/NCBI
32	Gendron R, Plamondon P and Grenier D: Binding of pro-matrix metalloproteinase 9 by Fusobacterium nucleatum subsp. nucleatum as a mechanism to promote the invasion of a reconstituted basement membrane. Infect Immun. 72:6160–6163. 2004. View Article : Google Scholar : PubMed/NCBI
33	Gustavo D, Glogowski CM, Eliezer M and Heinemann SF: Deletion of the α7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 29:8805–8815. 2009. View Article : Google Scholar : PubMed/NCBI
34	Maiti P, Manna J, Veleri S and Frautschy S: Molecular chaperone dysfunction in neurodegenerative diseases and effects of curcumin. Biomed Res Int. 2014:4950912014. View Article : Google Scholar : PubMed/NCBI
35	Qi Y, Dou DQ, Jiang H, Zhang BB, Qin WY, Kang K, Zhang N and Jia D: Arctigenin attenuates learning and memory deficits through PI3k/Akt/GSK-3β pathway reducing tau hyperphosphorylation in Aβ-induced AD mice. Planta Med. 83:51–56. 2017.PubMed/NCBI