<i>APOE</i> ε4 associates with microglial activation independently of Aβ plaques and tau tangles-Reference-Cited by-同舟云学术

APOE ε4 associates with microglial activation independently of Aβ plaques and tau tangles

Published:2023-04-07 Issue:14 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Ferrari-Souza João Pedro¹²^ORCID,Lussier Firoza Z.¹³^ORCID,Leffa Douglas T.¹⁴^ORCID,Therriault Joseph³^ORCID,Tissot Cécile¹³^ORCID,Bellaver Bruna¹²^ORCID,Ferreira Pâmela C. L.¹^ORCID,Malpetti Maura⁵^ORCID,Wang Yi-Ting³,Povala Guilherme¹²^ORCID,Benedet Andréa L.³⁶^ORCID,Ashton Nicholas J.⁶⁷⁸,Chamoun Mira³^ORCID,Servaes Stijn³^ORCID,Bezgin Gleb³⁹,Kang Min Su³¹⁰¹¹^ORCID,Stevenson Jenna³,Rahmouni Nesrine³,Pallen Vanessa³,Poltronetti Nina Margherita³,O’Brien John T.⁵¹²^ORCID,Rowe James B.⁵¹³^ORCID,Cohen Ann D.¹,Lopez Oscar L.¹⁴^ORCID,Tudorascu Dana L.¹,Karikari Thomas K.¹⁶¹⁵^ORCID,Klunk William E.¹,Villemagne Victor L.¹,Soucy Jean-Paul⁹,Gauthier Serge³,Souza Diogo O.²,Zetterberg Henrik⁶¹⁵¹⁶¹⁷¹⁸^ORCID,Blennow Kaj⁶¹⁵^ORCID,Zimmer Eduardo R.²¹⁹²⁰^ORCID,Rosa-Neto Pedro³^ORCID,Pascoal Tharick A.¹¹⁴^ORCID

Affiliation:

1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

2. Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

3. Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.

4. ADHD Outpatient Program and Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.

5. Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, UK.

6. Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

7. Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.

8. Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.

9. Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

10. Artificial Intelligence and Computational Neurosciences lab, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.

11. LC Campbell Cognitive Neurology Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.

12. Department of Psychiatry, University of Cambridge, Cambridge, UK.

13. MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.

14. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

15. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.

16. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

17. UK Dementia Research Institute at UCL, London, UK.

18. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.

19. Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

20. Graduate Program in Biological Sciences: Pharmacology and Therapeuctis, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Abstract

Animal studies suggest that the apolipoprotein E ε4 ( APOE ε4) allele is a culprit of early microglial activation in Alzheimer’s disease (AD). Here, we tested the association between APOE ε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [ 18 F]AZD4694), tau ([ 18 F]MK6240), and microglial activation ([ 11 C]PBR28). We found that APOE ε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOE ε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE ε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE ε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.ade1474

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