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  3. [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease

[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease

  • Nat Commun. 2022 Jul 19;13(1):4171. doi: 10.1038/s41467-022-30653-5.
Tharick A Pascoal 1 2 3 4,  Mira Chamoun 1,  Elad Lax 5 6,  Hsiao-Ying Wey 6,  Monica Shin 1,  Kok Pin Ng 1,  Min Su Kang 1 4,  Sulantha Mathotaarachchi 1,  Andrea L Benedet 1,  Joseph Therriault 1,  Firoza Z Lussier 1,  Frederick A Schroeder 7,  Jonathan M DuBois 7,  Baileigh G Hightower 7,  Tonya M Gilbert 7,  Nicole R Zürcher 7,  Changning Wang 7,  Robert Hopewell 4,  Mallar Chakravarty 8,  Melissa Savard 1,  Emilie Thomas 1,  Sara Mohaddes 1,  Sarah Farzin 8,  Alyssa Salaciak 8,  Stephanie Tullo 8,  A Claudio Cuello 6,  Jean-Paul Soucy 4,  Gassan Massarweh 4,  Heungsun Hwang 9,  Eliane Kobayashi 4,  Bradley T Hyman 10,  Bradford C Dickerson 7 9,  Marie-Christine Guiot 4,  Moshe Szyf 6,  Serge Gauthier 1,  Jacob M Hooker 7,  Pedro Rosa-Neto 11 12
Affiliations

Affiliations

  • 1 Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Faculty of Medicine, The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada.
  • 2 Departments of Psychiatry and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 3 Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 4 Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
  • 5 Department of Molecular Biology, Ariel University, Ariel, Israel.
  • 6 Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
  • 7 Neurology Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • 8 Departments of Biological and Biomedical Engineering and Psychiatry, Douglas Mental Health University Institute, Brain Imaging Centre, Montreal, QC, Canada.
  • 9 Department of Psychology, McGill University, Montreal, QC, Canada.
  • 10 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 11 Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Faculty of Medicine, The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada. pedro.rosa@mcgill.ca.
  • 12 Montreal Neurological Institute, McGill University, Montreal, QC, Canada. pedro.rosa@mcgill.ca.
PMID: 35853847 DOI: 10.1038/s41467-022-30653-5
Abstract

Alzheimer's disease (AD) is characterized by the brain accumulation of Amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of Amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for Amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1-3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated Amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of Amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human Amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.

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