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

Tharick A. Pascoal, Mira Chamoun, Elad Lax, Hsiao-Ying Wey, Monica Shin, Kok Pin Ng, Min Su Kang, Sulantha Mathotaarachchi, Andrea L. Benedet, Joseph Therriault, Firoza Z. Lussier, Frederick A. Schroeder, Jonathan M. DuBois, Baileigh G. Hightower, Tonya M. Gilbert, Nicole R. Zürcher, Changning Wang, Robert Hopewell, Mallar Chakravarty, Melissa Savard, Emilie Thomas, Sara Mohaddes, Sarah Farzin, Alyssa Salaciak, Stephanie Tullo, A. Claudio Cuello, Jean-Paul Soucy, Gassan Massarweh, Heungsun Hwang, Eliane Kobayashi, Bradley T. Hyman, Bradford C. Dickerson, Marie-Christine Guiot, Moshe Szyf, Serge Gauthier, Jacob M. Hooker and Pedro Rosa-Neto ()
Additional contact information
Tharick A. Pascoal: McGill University
Mira Chamoun: McGill University
Elad Lax: Ariel University
Hsiao-Ying Wey: McGill University
Monica Shin: McGill University
Kok Pin Ng: McGill University
Min Su Kang: McGill University
Sulantha Mathotaarachchi: McGill University
Andrea L. Benedet: McGill University
Joseph Therriault: McGill University
Firoza Z. Lussier: McGill University
Frederick A. Schroeder: Harvard Medical School
Jonathan M. DuBois: Harvard Medical School
Baileigh G. Hightower: Harvard Medical School
Tonya M. Gilbert: Harvard Medical School
Nicole R. Zürcher: Harvard Medical School
Changning Wang: Harvard Medical School
Robert Hopewell: McGill University
Mallar Chakravarty: Brain Imaging Centre
Melissa Savard: McGill University
Emilie Thomas: McGill University
Sara Mohaddes: McGill University
Sarah Farzin: Brain Imaging Centre
Alyssa Salaciak: Brain Imaging Centre
Stephanie Tullo: Brain Imaging Centre
A. Claudio Cuello: McGill University
Jean-Paul Soucy: McGill University
Gassan Massarweh: McGill University
Heungsun Hwang: McGill University
Eliane Kobayashi: McGill University
Bradley T. Hyman: Harvard Medical School
Bradford C. Dickerson: Harvard Medical School
Marie-Christine Guiot: McGill University
Moshe Szyf: McGill University
Serge Gauthier: McGill University
Jacob M. Hooker: Harvard Medical School
Pedro Rosa-Neto: McGill University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30653-5

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