Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Synapsin 1 Ameliorates Cognitive Impairment and Neuroinflammation in Rats with Alzheimer’s Disease: An Experimental and Bioinformatics Study

Author(s): Wei Ma, Kui Lu, Hua-Min Liang and Jin-Yuan Zhang*

Volume 20, Issue 9, 2023

Published on: 11 January, 2024

Page: [648 - 659] Pages: 12

DOI: 10.2174/0115672050276594231229050906

Price: $65

Open Access Journals Promotions 2
conference banner
Abstract

Background:: Alzheimer’s disease (AD) is a persistent neuropathological injury that manifests via neuronal/synaptic death, age spot development, tau hyperphosphorylation, neuroinflammation, and apoptosis. Synapsin 1 (SYN1), a neuronal phosphoprotein, is believed to be responsible for the pathology of AD.

Objective: This study aimed to elucidate the exact role of SYN1 in ameliorating AD and its potential regulatory mechanisms.

Methods: The AD dataset GSE48350 was downloaded from the GEO database, and SYN1 was focused on differential expression analysis and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. After establishing an AD rat model, they were treated with RNAi lentivirus to trigger SYN1 overexpression. The amelioration of SYN1 in AD-associated behavior was validated using multiple experiments (water maze test and object recognition test). SYN1’s repairing effect on the important factors in AD was confirmed by detecting the concentration of inflammatory factors (interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α), neurotransmitters (acetylcholine (ACh), dopamine (DA), and 5-hydroxytryptophan (5-HT)) and markers of oxidative stress (glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS)). Molecular biology experiments (qRT-PCR and western blot) were performed to examine AD-related signaling pathways after SYN1 overexpression.

Results: Differential expression analysis yielded a total of 545 differentially expressed genes, of which four were upregulated and 541 were downregulated. The enriched pathways were basically focused on synaptic functions, and the analysis of the protein– protein interaction network focused on the key genes in SYN1. SYN1 significantly improved the spatial learning and memory abilities of AD rats. This enhancement was reflected in the reduced escape latency of the rats in the water maze, the significantly extended dwell time in the third quadrant, and the increased number of crossings. Furthermore, the results of the object recognition test revealed reduced time for rats to explore familiar and new objects. After SYN1 overexpression, the cAMP signaling pathway was activated, the phosphorylation levels of the CREB and PKA proteins were elevated, and the secretion of neurotransmitters such as ACh, DA, and 5-HT was promoted. Furthermore, oxidative stress was suppressed, as supported by decreased levels of MDA and ROS. Regarding inflammatory factors, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in AD rats with SYN1 overexpression.

Conclusion: SYN1 overexpression improves cognitive function and promotes the release of various neurotransmitters in AD rats by inhibiting oxidative stress and inflammatory responses through cAMP signaling pathway activation. These findings may provide a theoretical basis for the targeted diagnosis and treatment of AD.

Keywords: Alzheimer’s disease (AD), synapsin 1 (SYN1), GEO database, oxidative stress, inflammatory response, cAMP signaling pathway.

« Previous Next »
[1]
2023 Alzheimer’s disease facts and figures. Alzheimers Dement., 2023, 19(4), 1598-1695.
[http://dx.doi.org/10.1002/alz.13016] [PMID: 36918389]
[2]
Beata, B.K.; Wojciech, J.; Johannes, K.; Piotr, L.; Barbara, M. Alzheimer’s disease—biochemical and psychological background for diagnosis and treatment. Int. J. Mol. Sci., 2023, 24(2), 1059.
[http://dx.doi.org/10.3390/ijms24021059] [PMID: 36674580]
[3]
Kelberman, M.A.; Anderson, C.R.; Chlan, E.; Rorabaugh, J.M.; McCann, K.E.; Weinshenker, D. Consequences of hyperphosphorylated tau in the locus coeruleus on behavior and cognition in a rat model of alzheimer’s disease. J. Alzheimers Dis., 2022, 86(3), 1037-1059.
[http://dx.doi.org/10.3233/JAD-215546] [PMID: 35147547]
[4]
Hunt, A.; Schönknecht, P.; Henze, M.; Seidl, U.; Haberkorn, U.; Schröder, J. Reduced cerebral glucose metabolism in patients at risk for Alzheimer’s disease. Psychiatry Res. Neuroimaging, 2007, 155(2), 147-154.
[http://dx.doi.org/10.1016/j.pscychresns.2006.12.003] [PMID: 17524628]
[5]
Olsson, B.; Lautner, R.; Andreasson, U.; Öhrfelt, A.; Portelius, E.; Bjerke, M.; Hölttä, M.; Rosén, C.; Olsson, C.; Strobel, G.; Wu, E.; Dakin, K.; Petzold, M.; Blennow, K.; Zetterberg, H. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Lancet Neurol., 2016, 15(7), 673-684.
[http://dx.doi.org/10.1016/S1474-4422(16)00070-3] [PMID: 27068280]
[6]
Sperling, R.A.; Donohue, M.C.; Raman, R.; Sun, C.K.; Yaari, R.; Holdridge, K.; Siemers, E.; Johnson, K.A.; Aisen, P.S. Association of factors with elevated amyloid burden in clinically normal older individuals. JAMA Neurol., 2020, 77(6), 735-745.
[http://dx.doi.org/10.1001/jamaneurol.2020.0387] [PMID: 32250387]
[7]
Zhang, X.; Wei, M.; Fan, J.; Yan, W.; Zha, X.; Song, H.; Wan, R.; Yin, Y.; Wang, W. Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons. Autophagy, 2021, 17(6), 1519-1542.
[http://dx.doi.org/10.1080/15548627.2020.1840796] [PMID: 33111641]
[8]
Maesako, M.; Zoltowska, K.M.; Berezovska, O. Synapsin 1 promotes Aβ generation via BACE1 modulation. PLoS One, 2019, 14(12), e0226368.
[http://dx.doi.org/10.1371/journal.pone.0226368] [PMID: 31830091]
[9]
Xiong, J.; Duan, H.; Chen, S.; Kessi, M.; He, F.; Deng, X.; Zhang, C.; Yang, L.; Peng, J.; Yin, F. Familial SYN1 variants related neurodevelopmental disorders in Asian pediatric patients. BMC Med. Genomics, 2021, 14(1), 182.
[http://dx.doi.org/10.1186/s12920-021-01028-4] [PMID: 34243774]
[10]
Perić, I.; Costina, V.; Djordjević, S.; Gass, P.; Findeisen, P.; Inta, D.; Borgwardt, S.; Filipović, D. Tianeptine modulates synaptic vesicle dynamics and favors synaptic mitochondria processes in socially isolated rats. Sci. Rep., 2021, 11(1), 17747.
[http://dx.doi.org/10.1038/s41598-021-97186-7] [PMID: 34493757]
[11]
Astillero-Lopez, V.; Gonzalez-Rodriguez, M.; Villar-Conde, S.; Flores-Cuadrado, A.; Martinez-Marcos, A.; Ubeda-Banon, I.; Saiz-Sanchez, D. Neurodegeneration and astrogliosis in the entorhinal cortex in Alzheimer’s disease: Stereological layer-specific assessment and proteomic analysis. Alzheimers Dement., 2022, 18(12), 2468-2480.
[http://dx.doi.org/10.1002/alz.12580] [PMID: 35142030]
[12]
Zhang, Q; Li, J; Weng, L. Identification and validation of aging-related genes in Alzheimer's disease. Front Neurosci., 2022, 16, 905722.
[http://dx.doi.org/10.3389/fnins.2022.905722]
[13]
Wang, Y; Chen, G; Shao, W. Identification of ferroptosis-related genes in alzheimer's disease based on bioinformatic analysis. Front Neurosci, 2022, 16, 823741.
[http://dx.doi.org/10.3389/fnins.2022.823741]
[14]
Li, J; Zhang, Y; Lu, T Identification of diagnostic genes for both Alzheimer's disease and Metabolic syndrome by the machine learning algorithm. Front Immunol, 2022, 13, 1037318.
[http://dx.doi.org/10.3389/fimmu.2022.1037318]
[15]
Zhang, R.; Xue, G.; Wang, S.; Zhang, L.; Shi, C.; Xie, X. Novel object recognition as a facile behavior test for evaluating drug effects in AβPP/PS1 Alzheimer’s disease mouse model. J. Alzheimers Dis., 2012, 31(4), 801-812.
[http://dx.doi.org/10.3233/JAD-2012-120151] [PMID: 22710911]
[16]
Bromley-Brits, K.; Deng, Y.; Song, W. Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J. Vis. Exp., 2011, 53, 53.
[http://dx.doi.org/10.3791/2920] [PMID: 21808223]
[17]
Weichenberger, C.X.; Palermo, A.; Pramstaller, P.P.; Domingues, F.S. Exploring approaches for detecting protein functional similarity within an orthology-based framework. Sci. Rep., 2017, 7(1), 381.
[http://dx.doi.org/10.1038/s41598-017-00465-5] [PMID: 28336965]
[18]
Ichiki, T.R. R&D of biodevice technology toward medical and pharmaceutical application 2016, 6(9), 5.
[19]
Ye, X.W.; Wang, H.L.; Cheng, S.Q.; Xia, L.J.; Xu, X.F.; Li, X.R. Network pharmacology-based strategy to investigate the pharmacologic mechanisms of coptidis rhizoma for the treatment of alzheimer's disease. Front Aging Neurosci, 2022, 14, 890046.
[http://dx.doi.org/10.3389/fnagi.2022.890046]
[20]
Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T.; Legeay, M.; Fang, T.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res., 2021, 49(D1), D605-D612.
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[21]
Doncheva, N.T.; Morris, J.H.; Gorodkin, J.; Jensen, L.J. Cytoscape stringApp: Network analysis and visualization of proteomics data. J. Proteome Res., 2019, 18(2), 623-632.
[http://dx.doi.org/10.1021/acs.jproteome.8b00702] [PMID: 30450911]
[22]
Guo, H.; Chen, R.; Li, P.; Yang, Q.; He, Y. ZBP1 mediates the progression of Alzheimer’s disease via pyroptosis by regulating IRF3. Mol. Cell. Biochem., 2023, 478(12), 2849-2860.
[http://dx.doi.org/10.1007/s11010-023-04702-6] [PMID: 36964897]
[23]
Liu, X.; Zhang, R.; Wu, Z.; Si, W.; Ren, Z.; Zhang, S.; Zhou, J.; Chen, D. miR‑134‑5p/Foxp2/Syn1 is involved in cognitive impairment in an early vascular dementia rat model. Int. J. Mol. Med., 2019, 44(5), 1729-1740.
[http://dx.doi.org/10.3892/ijmm.2019.4331] [PMID: 31545395]
[24]
Barnett, A; David, E; Rohlman, A Adolescent binge alcohol enhances early alzheimer's disease pathology in adulthood through proinflammatory neuroimmune activation. Front Pharmacol, 2022, 13, 884170.
[http://dx.doi.org/10.3389/fphar.2022.884170]
[25]
Saloner, R.; Paolillo, E.W.; Wojta, K.J.; Fonseca, C.; Gontrum, E.Q.; Lario-Lago, A.; Rabinovici, G.D.; Yokoyama, J.S.; Rexach, J.E.; Kramer, J.H.; Casaletto, K.B. Sex-specific effects of SNAP-25 genotype on verbal memory and Alzheimer’s disease biomarkers in clinically normal older adults. Alzheimers Dement., 2023, 19(8), 3448-3457.
[http://dx.doi.org/10.1002/alz.12989] [PMID: 36807763]
[26]
Pereira, J.B.; Janelidze, S.; Ossenkoppele, R.; Kvartsberg, H.; Brinkmalm, A.; Mattsson-Carlgren, N.; Stomrud, E.; Smith, R.; Zetterberg, H.; Blennow, K.; Hansson, O. Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease. Brain, 2021, 144(1), 310-324.
[http://dx.doi.org/10.1093/brain/awaa395] [PMID: 33279949]
[27]
McGrowder, D.A.; Miller, F.; Vaz, K.; Nwokocha, C.; Wilson-Clarke, C.; Anderson-Cross, M.; Brown, J.; Anderson-Jackson, L.; Williams, L.; Latore, L.; Thompson, R.; Alexander-Lindo, R. Cerebrospinal fluid biomarkers of alzheimer’s disease: Current evidence and future perspectives. Brain Sci., 2021, 11(2), 215.
[http://dx.doi.org/10.3390/brainsci11020215] [PMID: 33578866]
[28]
Chen, X.Q.; Zuo, X.; Becker, A.; Head, E.; Mobley, W.C. Reduced synaptic proteins and SNARE complexes in Down syndrome with Alzheimer’s disease and the Dp16 mouse Down syndrome model: Impact of APP gene dose. Alzheimers Dement., 2023, 19(5), 2095-2116.
[http://dx.doi.org/10.1002/alz.12835] [PMID: 36370135]
[29]
Chang, C.H.; Lin, C.H.; Lane, H.Y. Machine learning and novel biomarkers for the diagnosis of alzheimer’s disease. Int. J. Mol. Sci., 2021, 22(5), 2761.
[http://dx.doi.org/10.3390/ijms22052761] [PMID: 33803217]
[30]
Van Cauwenberghe, C.; Van Broeckhoven, C.; Sleegers, K. The genetic landscape of Alzheimer disease: Clinical implications and perspectives. Genet. Med., 2016, 18(5), 421-430.
[http://dx.doi.org/10.1038/gim.2015.117] [PMID: 26312828]
[31]
Abeysinghe, A; Deshapriya, R; Udawatte, C. Alzheimer's disease; a review of the pathophysiological basis and therapeutic interventions. Life Sci, 2020, 256, 117996.
[32]
Longhena, F; Faustini, G; Brembati, V; Pizzi, M; Benfenati, F; Bellucci, A An updated reappraisal of synapsins: Structure, function and role in neurological and psychiatric disorders. Neurosci Biobehav Rev, 2021, 130, 33-60.
[http://dx.doi.org/10.1016/j.neubiorev.2021.08.011]
[33]
Parenti, I; Leitao, E; Kuechler, A The different clinical facets of SYN1-related neurodevelopmental disorders. Front Cell Dev Biol, 2022, 10, 1019715.
[http://dx.doi.org/10.3389/fcell.2022.1019715]
[34]
Ramadan, W.S.; Alkarim, S. Ellagic acid modulates the amyloid precursor protein gene via superoxide dismutase regulation in the entorhinal cortex in an experimental alzheimer’s model. Cells, 2021, 10(12), 3511.
[http://dx.doi.org/10.3390/cells10123511] [PMID: 34944019]
[35]
Kamat, P.K.; Kalani, A.; Rai, S.; Swarnkar, S.; Tota, S.; Nath, C.; Tyagi, N. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of alzheimer’s disease: Understanding the therapeutics strategies. Mol. Neurobiol., 2016, 53(1), 648-661.
[http://dx.doi.org/10.1007/s12035-014-9053-6] [PMID: 25511446]
[36]
Lalut, J.; Karila, D.; Dallemagne, P.; Rochais, C. Modulating 5-HT 4 and 5-HT 6 receptors in Alzheimer’s disease treatment. Future Med. Chem., 2017, 9(8), 781-795.
[http://dx.doi.org/10.4155/fmc-2017-0031] [PMID: 28504917]
[37]
Jarosova, R.; Niyangoda, S.S.; Hettiarachchi, P.; Johnson, M.A. Impaired dopamine release and latent learning in alzheimer’s disease model zebrafish. ACS Chem. Neurosci., 2022, 13(19), 2924-2931.
[http://dx.doi.org/10.1021/acschemneuro.2c00484] [PMID: 36113115]
[38]
Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: Targeting the cholinergic system. Curr. Neuropharmacol., 2016, 14(1), 101-115.
[http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]
[39]
Liu, W.; Li, J.; Yang, M.; Ke, X.; Dai, Y.; Lin, H.; Wang, S.; Chen, L.; Tao, J. Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer’s disease. Alzheimers Res. Ther., 2022, 14(1), 53.
[http://dx.doi.org/10.1186/s13195-022-00994-w] [PMID: 35418161]
[40]
Tripathi, P.N.; Srivastava, P.; Sharma, P.; Tripathi, M.K.; Seth, A.; Tripathi, A.; Rai, S.N.; Singh, S.P.; Shrivastava, S.K. Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory. Bioorg. Chem., 2019, 85, 82-96.
[http://dx.doi.org/10.1016/j.bioorg.2018.12.017] [PMID: 30605887]
[41]
Srivastava, P.; Tripathi, P.N.; Sharma, P.; Rai, S.N.; Singh, S.P.; Srivastava, R.K.; Shankar, S.; Shrivastava, S.K. Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory. Eur. J. Med. Chem., 2019, 163, 116-135.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.049] [PMID: 30503937]
[42]
McGeer, P.L.; Schulzer, M.; McGeer, E.G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease. Neurology, 1996, 47(2), 425-432.
[http://dx.doi.org/10.1212/WNL.47.2.425] [PMID: 8757015]
[43]
Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G.M.; Cooper, N.R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B.L.; Finch, C.E.; Frautschy, S.; Griffin, W.S.; Hampel, H.; Hull, M.; Landreth, G.; Lue, L.; Mrak, R.; Mackenzie, I.R.; McGeer, P.L.; O’Banion, M.K.; Pachter, J.; Pasinetti, G.; Plata-Salaman, C.; Rogers, J.; Rydel, R.; Shen, Y.; Streit, W.; Strohmeyer, R.; Tooyoma, I.; Van Muiswinkel, F.L.; Veerhuis, R.; Walker, D.; Webster, S.; Wegrzyniak, B.; Wenk, G.; Wyss-Coray, T. Inflammation and Alzheimer’s disease. Neurobiol. Aging, 2000, 21(3), 383-421.
[http://dx.doi.org/10.1016/S0197-4580(00)00124-X] [PMID: 10858586]
[44]
Tam, K.Y.; Ju, Y. Pathological mechanisms and therapeutic strategies for Alzheimer’s disease. Neural Regen. Res., 2022, 17(3), 543-549.
[http://dx.doi.org/10.4103/1673-5374.320970] [PMID: 34380884]
[45]
Kumar, A; Singh, A. A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions. Front Pharmacol, 2015, 6, 206.
[http://dx.doi.org/10.3389/fphar.2015.00206]
[46]
Rai, S.N.; Singh, C.; Singh, A.; Singh, M.P.; Singh, B.K. Mitochondrial dysfunction: A potential therapeutic target to treat alzheimer’s disease. Mol. Neurobiol., 2020, 57(7), 3075-3088.
[http://dx.doi.org/10.1007/s12035-020-01945-y] [PMID: 32462551]
[47]
Gu, F.; Chauhan, V.; Chauhan, A. Glutathione redox imbalance in brain disorders. Curr. Opin. Clin. Nutr. Metab. Care, 2015, 18(1), 89-95.
[http://dx.doi.org/10.1097/MCO.0000000000000134] [PMID: 25405315]
[48]
Frijhoff, J.; Winyard, P.G.; Zarkovic, N.; Davies, S.S.; Stocker, R.; Cheng, D.; Knight, A.R.; Taylor, E.L.; Oettrich, J.; Ruskovska, T.; Gasparovic, A.C.; Cuadrado, A.; Weber, D.; Poulsen, H.E.; Grune, T.; Schmidt, H.H.H.W.; Ghezzi, P. Clinical relevance of biomarkers of oxidative stress. Antioxid. Redox Signal., 2015, 23(14), 1144-1170.
[http://dx.doi.org/10.1089/ars.2015.6317] [PMID: 26415143]
[49]
Ju, WK; Shim, MS; Kim, KY Inhibition of cAMP/PKA pathway protects optic nerve head astrocytes against oxidative stress by akt/bax phosphorylation-mediated Mfn1/2 oligomerization. Oxid Med Cell Longev, 2019, 2019, 8060962.
[50]
Yu, S.; Doycheva, D.M.; Gamdzyk, M.; Yang, Y.; Lenahan, C.; Li, G.; Li, D.; Lian, L.; Tang, J.; Lu, J.; Zhang, J.H. Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats. J. Neuroinflammation, 2021, 18(1), 26.
[http://dx.doi.org/10.1186/s12974-021-02078-2] [PMID: 33468172]
[51]
Jankowska, A.; Pawłowski, M.; Chłoń-Rzepa, G. Diabetic theory in anti-alzheimer’s drug research and development. Part 2: Therapeutic potential of cAMP-specific phosphodiesterase inhibitors. Curr. Med. Chem., 2021, 28(18), 3535-3553.
[http://dx.doi.org/10.2174/0929867327666200917125857] [PMID: 32940168]
[52]
Viña, D.; Seoane, N.; Vasquez, E.C.; Campos-Toimil, M. cAMP compartmentalization in cerebrovascular endothelial cells: New therapeutic opportunities in alzheimer’s disease. Cells, 2021, 10(8), 1951.
[http://dx.doi.org/10.3390/cells10081951] [PMID: 34440720]
[53]
Sharma, V.K.; Singh, T.G. CREB: A multifaceted target for alzheimer’s disease. Curr. Alzheimer Res., 2021, 17(14), 1280-1293.
[http://dx.doi.org/10.2174/1567205018666210218152253] [PMID: 33602089]
[54]
Balkrishna, A; Bhattacharya, K; Shukla, S; Varshney, A. Neuroprotection by polyherbal medicine divya-medha-vati against scopolamine-induced cognitive impairment through modulation of oxidative stress, acetylcholine activity, and cell signaling. Mol Neurobiol, 2023, 1-20.

Rights & Permissions Print Cite
Article Metrics
48
2
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy