[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 SavardEmilie 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, Pedro Rosa-Neto

פרסום מחקרי: פרסום בכתב עתמאמרביקורת עמיתים

20 ציטוטים ‏(Scopus)

תקציר

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.

שפה מקוריתאנגלית
מספר המאמר4171
כתב עתNature Communications
כרך13
מספר גיליון1
מזהי עצם דיגיטלי (DOIs)
סטטוס פרסוםפורסם - דצמ׳ 2022

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