[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
  • 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. [email protected].
  • 12. Montreal Neurological Institute, McGill University, Montreal, QC, Canada. [email protected].
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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