Friday, 6th December 2019

Genetic bases of Alzheimer's Disease: Genomic study of pathogenic cell models



María Jesús Bullido




Research summary:

In the last years our group has focused on the search of risk factors and/or genes involved in the Alzheimers disease (AD), developing cellular models to obtain candidates that are then validated through genetic association studies in patients. One of the main objectives of the group is to establish the involvement in the pathogenesis of AD of two factors associated with aging, oxidative stress (OS) and infection by HSV 1.

-------- Fig01-300
  Oxidative stress produces the accumulation of APP protein and its carboxi and amino terminal fragments in SK N MC neuronal cells.

We have found that in the cell models OS regulates the traffic, degradation and proteolytic processing of the peptide Aβ precursor protein (APP), and that this regulation involves the two main cellular proteolytic systems: ubiquitin/proteasome and autophagy/lysosome. On the other hand, HSV-1 is able to reproduce most of the anomalies found in the brains of AD patients, as the hyperphosphorylation of tau protein and alterations of the autophagic process that lead to the intracellular accumulation of Aβ; these effects are increased in the presence of OS.
After the genomic analysis of the cell models, we have focused on the list of genes which expression is modulated by HSV 1 in the presence of OS because this is similar to the infection in aged people for their functional validation and genetic risk association studies. The "cytokine-mediated inflammation" function is highly enriched in this list, which is consistent with the findings of the latest genome wide association studies (GWAs) and suggests that HSV 1 may participate in the pathogenesis of sporadic AD.

Other works of the group during this period include the analysis of cellular models of monogenic AD, and the participation in collaborative genetic association studies, mainly with groups of CIBERNED and as part of the European consortium EADI, which are revealing novel AD risk factors..



  • Kristen H, Sastre I, Muñoz-Galdeano T, Recuero M,Aldudo J, Bullido MJ (2018) The lysosome system is severely impaired in a cellular model of neurodegeneration induced by HSV-1 and oxidative stress. Neurobiol Aging 68: 5-17.
    Kristen H, Santana S, Sastre I, Recuero M, Bullido MJ, Aldudo J (2015) Herpes simplex virus type 2 infection induces AD-like neurodegeneration markers in human neuroblastoma cells. Neurobiol Aging 36(10): 2737-2747.
  • Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW et al. Bullido MJ (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49(9):1373-1384.
  • Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, Letenneur L, Lövheim H, Mancuso R, Miklossy J, Otth C, Palamara AT, Perry G, Preston C, Pretorius E, Strandberg T, Tabet N, Taylor-Robinson SD, Whittum-Hudson JA (2016) Microbes and Alzheimer's Disease. J Alzheimers Dis 51(4): 979-84.
  • Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, et al. (2016) Microbes and Alzheimer's disease. J Alzheimers Dis 51(4): 979-984.
  • Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, et al. Bullido MJ. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21(1): 108-17.
  • Pastor P, Moreno F, Clarimón J, Ruiz A, Combarros O, Calero M, De Munain AL, Bullido MJ, et al (2015). MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE ε 4 noncarriers: Results from the dementia genetics Spanish consortium. J Alzheimers Dis 49(2): 343-352.
  • Jones L, Lambert JC, Wang LS, Choi SH, Harold D, Vedernikov A, et al. Bullido MJ (2015) Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimers & Dementia 11(6): 658-671.
  • Ruiz A, Dols-Icardo O, Bullido MJ, Pastor P, Rodríguez-Rodríguez E, et al. (2014) Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia. Neurobiol Aging 35: 444 e1-4.
  • Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, et al. (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45: 1452-8.
  • Santana S, Sastre I, Recuero M, Bullido MJ, Aldudo J (2013) Oxidative stress enhances neurodegeneration markers induced by herpes simplex virus type 1 infection in human neuroblastoma cells. PLoS One 8: e75842.
  • Recuero M, Munive VA, Sastre I, Aldudo J, Valdivieso F, et al. (2013) A free radical-generating system regulates AbetaPP metabolism/processing: involvement of the ubiquitin/proteasome and autophagy/lysosome pathways. J Alzheimers Dis 34: 637-647.
  • Santana S, Recuero M, Bullido MJ, Valdivieso F, Aldudo J (2012) Herpes simplex virus type I induces the accumulation of intracellular beta-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. Neurobiol Aging 33: 430 e419-433.
  • Santana S, Bullido MJ, Recuero M, Valdivieso F, Aldudo J (2012) Herpes simplex virus type I induces an incomplete autophagic response in human neuroblastoma cells. J Alzheimers Dis 30: 815-831.
  • Recuero M, Munoz T, Aldudo J, Subias M, Bullido MJ, et al. (2010) A free radical-generating system regulates APP metabolism/processing. FEBS Lett 584: 4611-4618.
  • Recuero M, Vicente MC, Martinez-Garcia A, Ramos MC, Carmona-Saez P, et al. (2009) A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease. Aging Cell 8: 128-139.




- Fundación Madrid+D. Premio a las mejores patentes; accésit. (2011)
- Sociedad Madrileña de Neurología. Premio Ramón y Cajal de Investigación básica (2011)

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