Abstract
Alzheimer’s disease (AD) is a progressive neuroinflammatory and neurodegenerative disorder that affects different regions of the brain. Its pathophysiology includes the accumulation of β-amyloid protein, formation of neurofibrillary tangles, and inflammatory processes. Genetic factors are involved in the onset of AD, but they are not fully elucidated. Identification of gene expression in encephalic tissues of patients with AD may help elucidate its development. Our objectives were to characterize and compare the gene expression of CDK10, CDK11, FOXO1, and FOXO3 in encephalic tissue samples from AD patients and elderly controls, from the auditory cortex and cerebellum. RT-qPCR was used on samples from 82 individuals (45 with AD and 37 controls). We observed a statistically significant increase in CDK10 (p = 0.029*) and CDK11 (p = 0.048*) gene expression in the AD group compared to the control, which was most evident in the cerebellum. Furthermore, the Spearman test demonstrated the presence of a positive correlation of gene expression both in the auditory cortex in the AD group (r = 0.046/p = 0.004) and control group (r = 0.454/p = 0.005); and in the cerebellum in the AD group (r = 0.654 /p < 0.001). There was no statistically significant difference and correlation in the gene expression of FOXO1 and FOXO3 in the AD group and the control. In conclusion, CDK10 and CDK11 have high expression in AD patients compared to control, and they present a positive correlation of gene expression in the analyzed groups and tissues, which suggests that they play an important role in the pathogenesis of AD.
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References
Bajić VP, Su B, Lee HG et al (2011) Mislocalization of CDK11/PITSLRE, a regulator of the G2/M phase of the cell cycle, in Alzheimer disease. Cell Mol Biol Lett 16:359. https://doi.org/10.2478/S11658-011-0011-2
Bayat S, Babulal GM, Schindler SE et al (2021) (2021) GPS driving: a digital biomarker for preclinical Alzheimer disease. Alzheimer’s Res Ther 131(13):1–9. https://doi.org/10.1186/S13195-021-00852-1
Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Review article: Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23:213–227
Bhansali RS, Rammohan M, Lee P et al (2021) DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3. J Clin Invest. https://doi.org/10.1172/JCI135937
Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–357. https://doi.org/10.1016/S0197-4580(97)00056-0
da Costa IB, de Labio RW, Rasmussen LT et al (2017) Change in INSR, APBA2 and IDE gene expressions in brains of Alzheimer’s disease patients. Curr Alzheimer Res. https://doi.org/10.2174/1567205014666170203100734
de Labio R, Rasmussen L, Mizumoto I et al (2014) PSEN1 and PSEN2 gene expression in Alzheimer’s disease brain: a new approach. J Alzheimer’s Dis 42:757–760. https://doi.org/10.3233/JAD-140033
Fluteau A, Ince PG, Minett T et al (2015) The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain. Neurosci Lett. https://doi.org/10.1016/j.neulet.2015.10.001
Fukasawa JT, de Labio RW, Rasmussen LT et al (2017) CDK5 and MAPT gene expression in Alzheimer’s disease brain samples. Curr Alzheimer Res 15:182–186. https://doi.org/10.2174/1567205014666170713160407
Herculano-Houzel S (2010) Coordinated scaling of cortical and cerebellar numbers of neurons. Front Neuroanat 0:12. https://doi.org/10.3389/FNANA.2010.00012/BIBTEX
Hoxha E, Lippiello P, Zurlo F et al (2018) The emerging role of altered cerebellar synaptic processing in Alzheimer’s disease. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2018.00396
Jacobs HIL, Hopkins DA, Mayrhofer HC et al (2018) The cerebellum in Alzheimer’s disease: evaluating its role in cognitive decline. Brain 141:37–47. https://doi.org/10.1093/BRAIN/AWX194
Kanekiyo T, Xu H, Bu G (2014) ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 81:740. https://doi.org/10.1016/J.NEURON.2014.01.045
Kheiri G, Dolatshahi M, Rahmani F, Rezaei N (2019) Role of p38/MAPKs in Alzheimer’s disease: implications for amyloid beta toxicity targeted therapy. Rev Neurosci 30:9–30. https://doi.org/10.1515/REVNEURO-2018-0008
Kinney JW, Bemiller SM, Murtishaw AS et al (2018) Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv 4:575. https://doi.org/10.1016/J.TRCI.2018.06.014
Kovacs DM, Fausett HJ, Page KJ et al (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat Med 2:224–229. https://doi.org/10.1038/nm0296-224
Koziol LF, Budding D, Andreasen N et al (2014) Consensus paper: the cerebellum’s role in movement and cognition. Cerebellum 13:151–177. https://doi.org/10.1007/S12311-013-0511-X
Lim KH, Kim SH, Yang S et al (2021) Advances in multiplex PCR for Alzheimer’s disease diagnostics targeting CDK genes. Neurosci Lett. https://doi.org/10.1016/j.neulet.2021.135715
Lim S, Kaldis P (2013) Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 140:3079–3093
Liu X, Cheng C, Shao B et al (2012) CDK11 p58 promotes rat astrocyte inflammatory response via activating p38 and JNK pathways induced by lipopolysaccharide. Neurochem Res 37:563–573. https://doi.org/10.1007/s11064-011-0643-7
Manolopoulos KN, Klotz L-O, Korsten P et al (2010) Linking Alzheimer’s disease to insulin resistance: the FoxO response to oxidative stress. Mol Psychiatry 1511(15):1046–1052. https://doi.org/10.1038/mp.2010.17
Masters CL, Bateman R, Blennow K et al (2015) Alzheimer’s disease. Nat Rev Dis Prim 1:1–18
Mei M, Su B, Harrison K et al (2006) Distribution, levels and phosphorylation of Raf-1 in Alzheimer’s disease. J Neurochem 99:1377–1388. https://doi.org/10.1111/j.1471-4159.2006.04174.x
Murtaza G, Khan AK, Rashid R et al (2017) FOXO transcriptional factors and long-term living. Oxid Med Cell Longev. https://doi.org/10.1155/2017/3494289
Paroni G, Seripa D, Fontana A et al (2014) FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer’s disease. Clin Interv Aging 9:1783–1791. https://doi.org/10.2147/CIA.S64758
Pradhan R, Yadav SK, Prem NN et al (2020) Serum FOXO3A: a ray of hope for early diagnosis of Alzheimer’s disease. Mech Ageing Dev. https://doi.org/10.1016/j.mad.2020.111290
Puig B, Gómez-Isla T, Ribé E et al (2004) Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding βA plaques in APP Tg2576 mice. Neuropathol Appl Neurobiol 30:491–502. https://doi.org/10.1111/j.1365-2990.2004.00569.x
Rasmussen L, de Labio R, Viani G et al (2015) Differential expression of ribosomal genes in brain and blood of Alzheimer’s disease patients. Curr Alzheimer Res. https://doi.org/10.2174/1567205012666151027124017
Salmon DP (2012) Neuropsychological features of mild cognitive impairment and preclinical Alzheimer’s disease. Curr Top Behav Neurosci 10:187–212. https://doi.org/10.1007/7854_2011_171
Santo EE, Paik J (2018) FOXO in neural cells and diseases of the nervous system. Curr Top Dev Biol 127:105–118
Shen Y, Ye B, Chen P et al (2018) Cognitive decline, dementia, Alzheimer’s disease and presbycusis: examination of the possible molecular mechanism. Front Neurosci 12:394
Shi C, Viccaro K, Lee H, Shah K (2016) Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer’s disease models. J Cell Sci 129:1815. https://doi.org/10.1242/JCS.185009
Singh-Bains MK, Linke V, Austria MDR et al (2019) Altered microglia and neurovasculature in the Alzheimer’s disease cerebellum. Neurobiol Dis. https://doi.org/10.1016/J.NBD.2019.104589
Soureshjani FH, Kheirollahi M, Yaghmaei P, Fattahjadnematalahi S (2021) Possible preventive effect of donepezil and hyoscyamoside by reduction of plaque formation and neuroinflammation in Alzheimer’s disease. Int J Prev Med 12:66. https://doi.org/10.4103/IJPVM.IJPVM_143_19
Stotani S, Giordanetto F, Medda F (2016) DYRK1A inhibition as potential treatment for Alzheimer’s disease. Future Med Chem 8:681–696
Turner PR, O’Connor K, Tate WP, Abraham WC (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70:1–32
Xu M, Zhang DF, Luo R et al (2018) A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer’s disease. Alzheimer’s Dement 14:215–229. https://doi.org/10.1016/j.jalz.2017.08.012
Xu W, Tan L, Wang HF et al (2015) Meta-analysis of modifiable risk factors for Alzheimer’s disease. J Neurol Neurosurg Psychiatry 86:1299–1306. https://doi.org/10.1136/jnnp-2015-310548
Yeh C-W, Kao S-H, Cheng Y-C, Hsu L-S (2013) Knockdown of cyclin-dependent kinase 10 (cdk10) gene impairs neural progenitor survival via modulation of raf1a gene expression*. J Biol Chem 288:27927–27939. https://doi.org/10.1074/JBC.M112.420265
Yu L, Hu J, Shi C et al (2021) The causal role of auditory cortex in auditory working memory. Elife. https://doi.org/10.7554/ELIFE.64457
Zhang W, Bai S, Yang J et al (2020) FoxO1 overexpression reduces Aβ production and tau phosphorylation in vitro. Neurosci Lett. https://doi.org/10.1016/j.neulet.2020.135322
Acknowledgements
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—[Finance Code 001] and [Grant number: 88887.609695/2021-00]; São Paulo Research Foundation (FAPESP)—[Grant number: 2021/12017-1]; and Marilia Medical School (FAMEMA).
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This work was supported by the São Paulo Research Foundation (FAPESP) in Brazil under Grant Number 2021/12017-1.
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Conceptualization and supervision: SLMP. Statistical Analysis: EFC. Methodology: MF; RWdL, and GT. Writing: BMF and SLMP. Review and/or Revision of the manuscript: LTR, ESC, and MdACS.
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The present research was approved by the Research Ethics Committee of Marilia Medical School (Famema) Number 823.72, under the responsibility of principal investigator Spencer Luiz Marques Payão, PhD.
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Fredi, B.M., De Labio, R.W., Rasmussen, L.T. et al. CDK10, CDK11, FOXO1, and FOXO3 Gene Expression in Alzheimer’s Disease Encephalic Samples. Cell Mol Neurobiol 43, 2953–2962 (2023). https://doi.org/10.1007/s10571-023-01341-9
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DOI: https://doi.org/10.1007/s10571-023-01341-9