Nogo‑66 promotes β‑amyloid protein secretion via NgR/ROCK‑dependent BACE1 activation

Xie,Qing-Qing; Feng,Xiao; Huang,Yi-Υun; Fang,Nian; Yi,Hua; Wang,Zi-Jian; Cao,Qiao-Υu; Lou,Guo-Feng; Pan,Jun-Ping; Hu,Yang; Li,Fang-Cheng; Zheng,Qing; Xiao,Fei

doi:10.3892/mmr.2021.11827

Nogo‑66 promotes β‑amyloid protein secretion via NgR/ROCK‑dependent BACE1 activation

Authors:
- Qing-Qing Xie
- Xiao Feng
- Yi-Υun Huang
- Nian Fang
- Hua Yi
- Zi-Jian Wang
- Qiao-Υu Cao
- Guo-Feng Lou
- Jun-Ping Pan
- Yang Hu
- Fang-Cheng Li
- Qing Zheng
- Fei Xiao
View Affiliations

Affiliations: Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Department of Microbiology and Biochemical Pharmacy, School of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Department of Pathology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 511436, P.R. China, Department of Clinical Molecular Biology, Akershus University Hospital, University of Oslo, 1478 Lørenskog, Norway, Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510632, P.R. China
Published online on: January 5, 2021 https://doi.org/10.3892/mmr.2021.11827
Article Number: 188
Copyright: © Xie 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

The generation of β‑amyloid protein (Aβ) is considered a key step in the pathogenesis of Alzheimer's disease (AD) and the regulation of its production is an important therapeutic strategy. It was hypothesized in the present study that Nogo‑A may be involved in AD and may regulate the generation of Aβ. Nogo‑A is known to act as a major inhibitor of neuron regeneration in the adult central nervous system. A recent study indicated that Nogo‑A is associated with AD; however, the underlying effect and molecular mechanisms remain largely elusive. In the present study, the potential effects of Nogo‑A on AD were investigated. ELISA was used to detect the levels of Aβ, enzymatic activity detection kits were used to determine the activity of secretase enzymes in amyloid precursor protein (APP) metabolism, and western blot analysis was used to detect the expression levels of proteins associated with the APP processing and Nogo‑A/Nogo‑66 receptor (NgR) signaling pathways. The results revealed that Nogo‑66, the major inhibitory region of Nogo‑A, promoted neuronal Aβ secretion by increasing the activity of β‑secretase 1 via the NgR/Rho‑associated coiled‑coil containing kinases pathway in a dose‑dependent manner. The present data suggested that Nogo‑A may facilitate the onset and development of AD by promoting Aβ secretion, providing information on a potential novel target for AD therapy.

View Figures

View References

1	Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA and Fang EF: Mitophagy and Alzheimer's disease: Cellular and molecular mechanisms. Trends Neurosci. 40:151–166. 2017. View Article : Google Scholar : PubMed/NCBI
2	Stephenson-Jones M, Yu K, Ahrens S, Tucciarone JM, van Huijstee AN, Mejia LA, Penzo MA, Tai LH, Wilbrecht L and Li B: A basal ganglia circuit for evaluating action outcomes. Nature. 539:289–293. 2016. View Article : Google Scholar : PubMed/NCBI
3	Pereira JB, Janelidze S, Ossenkoppele R, Kvartsberg H, Brinkmalm A, Mattsson-Carlgren N, Stomrud E, Smith R, Zetterberg H, Blennow K, et al: Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease. Brain awaa395. 2020. View Article : Google Scholar
4	Hardy J and Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297:353–356. 2002. View Article : Google Scholar : PubMed/NCBI
5	Lin Y-T, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, et al: APOE4 causes widespread molecular and cellular alterations associated with Alzheimer's disease phenotypes in human iPSC-derived brain cell types. Neuron. 98:1141–1154.e7. 2018. View Article : Google Scholar : PubMed/NCBI
6	Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, et al: Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 22:401–412. 2019. View Article : Google Scholar : PubMed/NCBI
7	Lautrup S, Sinclair DA, Mattson MP and Fang EF: NAD⁺ in brain aging and neurodegenerative disorders. Cell Metab. 30:630–655. 2019. View Article : Google Scholar : PubMed/NCBI
8	Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, et al: Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model. Nat Neurosci. 22:719–728. 2019. View Article : Google Scholar : PubMed/NCBI
9	Oertle T, van der Haar ME, Bandtlow CE, Robeva A, Burfeind P, Buss A, Huber AB, Simonen M, Schnell L, Brösamle C, et al: Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J Neurosci. 23:5393–5406. 2003. View Article : Google Scholar : PubMed/NCBI
10	Huebner EA and Strittmatter SM: Axon regeneration in the peripheral and central nervous systems. Results Probl Cell Differ. 48:339–351. 2009.PubMed/NCBI
11	Grandpré T and Strittmatter SM: Nogo: A molecular determinant of axonal growth and regeneration. Neuroscientist. 7:377–386. 2001. View Article : Google Scholar : PubMed/NCBI
12	Mosyak L, Wood A, Dwyer B, Buddha M, Johnson M, Aulabaugh A, Zhong X, Presman E, Benard S, Kelleher K, et al: The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. J Biol Chem. 281:36378–36390. 2006. View Article : Google Scholar : PubMed/NCBI
13	Gil V, Nicolas O, Mingorance A, Ureña JM, Tang BL, Hirata T, Sáez-Valero J, Ferrer I, Soriano E and del Río JA: Nogo-A expression in the human hippocampus in normal aging and in Alzheimer disease. J Neuropathol Exp Neurol. 65:433–444. 2006. View Article : Google Scholar : PubMed/NCBI
14	Fang Y, Yao L, Li C, Wang J, Wang J, Chen S, Zhou XF and Liao H: The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice. J Neuroinflammation. 13:562016. View Article : Google Scholar : PubMed/NCBI
15	Xiao F, Lin LF, Cheng X, Gao Q and Luo HM: Nogo-66 receptor activation inhibits neurite outgrowth and increases β-amyloid protein secretion of cortical neurons. Mol Med Rep. 5:619–624. 2012.PubMed/NCBI
16	Dai X, Sun Z, Liang R, Li Y, Luo H, Huang Y, Chen M, Su Z and Xiao F: Recombinant Nogo-66 via soluble expression with SUMO fusion in Escherichia coli inhibits neurite outgrowth in vitro. Appl Microbiol Biotechnol. 99:5997–6007. 2015. View Article : Google Scholar : PubMed/NCBI
17	zur Nedden S, Doney AS and Frenguelli BG: Modulation of intracellular ATP determines adenosine release and functional outcome in response to metabolic stress in rat hippocampal slices and cerebellar granule cells. J Neurochem. 128:111–124. 2014. View Article : Google Scholar : PubMed/NCBI
18	Gao R, Wang Y, Pan Q, Huang G, Li N, Mou J and Wang D: Fuzhisan, a chinese herbal medicine, suppresses beta-secretase gene transcription via upregulation of SIRT1 expression in N2a-APP695 cells. Int J Clin Exp Med. 8:7231–7240. 2015.PubMed/NCBI
19	Jin SG, Ryu HH, Li SY, Li CH, Lim SH, Jang WY and Jung S: Nogo-A inhibits the migration and invasion of human malignant glioma U87MG cells. Oncol Rep. 35:3395–3402. 2016. View Article : Google Scholar : PubMed/NCBI
20	Yan J, Zhou X, Guo JJ, Mao L, Wang YJ, Sun J, Sun LX, Zhang LY, Zhou XF and Liao H: Nogo-66 inhibits adhesion and migration of microglia via GTPase Rho pathway in vitro. J Neurochem. 120:721–731. 2012. View Article : Google Scholar : PubMed/NCBI
21	GrandPré T, Nakamura F, Vartanian T and Strittmatter SM: Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature. 403:439–444. 2000. View Article : Google Scholar : PubMed/NCBI
22	Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F and Schwab ME: Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature. 403:434–439. 2000. View Article : Google Scholar : PubMed/NCBI
23	Niederöst B, Oertle T, Fritsche J, McKinney RA and Bandtlow CE: Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. J Neurosci. 22:10368–10376. 2002. View Article : Google Scholar : PubMed/NCBI
24	Zhou X, Hu X, He W, Tang X, Shi Q, Zhang Z and Yan R: Interaction between amyloid precursor protein and Nogo receptors regulates amyloid deposition. FASEB J. 25:3146–3156. 2011. View Article : Google Scholar : PubMed/NCBI
25	Park JH, Gimbel DA, GrandPre T, Lee JK, Kim JE, Li W, Lee DH and Strittmatter SM: Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition. J Neurosci. 26:1386–1395. 2006. View Article : Google Scholar : PubMed/NCBI
26	Jiang R, Wu XF, Wang B, Guan RX, Lv LM, Li AP, Lei L, Ma Y, Li N, Li QF, et al: Reduction of NgR in perforant path decreases amyloid-β peptide production and ameliorates synaptic and cognitive deficits in APP/PS1 mice. Alzheimers Res Ther. 12:472020. View Article : Google Scholar : PubMed/NCBI
27	He W, Lu Y, Qahwash I, Hu X-Y, Chang A and Yan R: Reticulon family members modulate BACE1 activity and amyloid-β peptide generation. Nat Med. 10:959–965. 2004. View Article : Google Scholar : PubMed/NCBI
28	Murayama KS, Kametani F, Saito S, Kume H, Akiyama H and Araki W: Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid β-protein. Eur J Neurosci. 24:1237–1244. 2006. View Article : Google Scholar : PubMed/NCBI
29	Masliah E, Xie F, Dayan S, Rockenstein E, Mante M, Adame A, Patrick CM, Chan AF and Zheng B: Genetic deletion of Nogo/Rtn4 ameliorates behavioral and neuropathological outcomes in amyloid precursor protein transgenic mice. Neuroscience. 169:488–494. 2010. View Article : Google Scholar : PubMed/NCBI
30	Xu W, Xiao P, Fan S, Chen Y, Huang W, Chen X, Liu G, Dang C, Zeng J and Xing S: Blockade of Nogo-A/Nogo-66 receptor 1 (NgR1) inhibits autophagic activation and prevents secondary neuronal damage in the thalamus after focal cerebral infarction in hypertensive rats. Neuroscience. 431:103–114. 2020. View Article : Google Scholar : PubMed/NCBI
31	Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC, et al: Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science. 302:1215–1217. 2003. View Article : Google Scholar : PubMed/NCBI
32	Herskowitz JH, Feng Y, Mattheyses AL, Hales CM, Higginbotham LA, Duong DM, Montine TJ, Troncoso JC, Thambisetty M, Seyfried NT, et al: Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer's disease mouse model. J Neurosci. 33:19086–19098. 2013. View Article : Google Scholar : PubMed/NCBI