2. Academic Validation
  3. LAMP2 deficiency attenuates the neurodegeneration markers induced by HSV-1 infection

LAMP2 deficiency attenuates the neurodegeneration markers induced by HSV-1 infection

  • Neurochem Int. 2021 Jun:146:105032. doi: 10.1016/j.neuint.2021.105032.
Henrike Kristen 1,  Isabel Sastre 1,  Sara Aljama 2,  Maria Fuentes 2,  Maria Recuero 3,  Ana Frank-García 4,  Angel Martin 4,  Pascual Sanchez-Juan 5,  Carmen Lage 5,  Maria J Bullido 6,  Jesus Aldudo 7
Affiliations

Affiliations

  • 1 Centro de Biologia Molecular "Severo Ochoa" (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • 2 Centro de Biologia Molecular "Severo Ochoa" (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain.
  • 3 Centro de Biologia Molecular "Severo Ochoa" (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IdiPAZ (Hospital Universitario La Paz - Universidad Autónoma de Madrid), Madrid, Spain.
  • 4 Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IdiPAZ (Hospital Universitario La Paz - Universidad Autónoma de Madrid), Madrid, Spain.
  • 5 Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Hospital Universitario Marqués de Valdecilla-IDIVAL-UC, Santander, Spain.
  • 6 Centro de Biologia Molecular "Severo Ochoa" (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IdiPAZ (Hospital Universitario La Paz - Universidad Autónoma de Madrid), Madrid, Spain. Electronic address: [email protected].
  • 7 Centro de Biologia Molecular "Severo Ochoa" (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IdiPAZ (Hospital Universitario La Paz - Universidad Autónoma de Madrid), Madrid, Spain. Electronic address: [email protected].
PMID: 33781848 DOI: 10.1016/j.neuint.2021.105032
Abstract

Mounting evidence suggests a major role of infectious agents in the pathogenesis of sporadic Alzheimer's disease (AD). Among them, herpes simplex virus type 1 (HSV-1) Infection has emerged as a major factor in the etiology of AD. HSV-1 is able to induce some of the main alterations of the disease such as hyperphosphorylation of Tau Protein and accumulation of Amyloid-β peptide. Functional genomic analysis of a cell model of HSV-1 Infection and oxidative stress developed in our laboratory revealed lysosomal system to be the main pathway altered, and the lysosome-associated membrane protein 2 (LAMP2) gene one of the most strongly modulated genes. The aim of this work is to study LAMP2 as an AD candidate gene and to investigate its role in the neurodegeneration induced by HSV-1 using a LAMP2 knockdown cell model. LAMP2 deficiency led to a significant reduction of viral DNA replication and formation of infectious particles. In addition, tau hyperphosphorylation and inhibition of Aβ secretion induced by the virus were attenuated by the absence of LAMP2. Finally, genetic association studies revealed LAMP2 genetic variants to be associated with AD risk. In summary, our data indicate that LAMP2 could be a suitable candidate to mediate the AD-like phenotype caused by HSV-1.

Keywords

Alzheimer's disease; Genetic association; HSV-1 infection; Herpesvirus; LAMP2; Lysosome; Neurodegeneration.

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