Temporal progression of tau pathology and neuroinflammation in a rhesus monkey model of Alzheimer's disease.

Autor: Beckman D; California National Primate Research Center, University of California Davis, Davis, California, USA., Diniz GB; California National Primate Research Center, University of California Davis, Davis, California, USA., Ott S; California National Primate Research Center, University of California Davis, Davis, California, USA., Hobson B; California National Primate Research Center, University of California Davis, Davis, California, USA.; Department of Radiology, School of Medicine, University of California Davis, Sacramento, California, USA., Chaudhari AJ; California National Primate Research Center, University of California Davis, Davis, California, USA.; Department of Radiology, School of Medicine, University of California Davis, Sacramento, California, USA., Muller S; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, Arizona, USA., Chu Y; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, Arizona, USA., Takano A; Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA., Schwarz AJ; Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA., Yeh CL; Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA., McQuade P; Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA., Chakrabarty P; Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA., Kanaan NM; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA., Quinton MS; Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA., Simen AA; Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA., Kordower JH; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, Arizona, USA.; Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA., Morrison JH; California National Primate Research Center, University of California Davis, Davis, California, USA.; Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, USA.
Jazyk: angličtina
Zdroj: Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2024 Aug; Vol. 20 (8), pp. 5198-5219. Date of Electronic Publication: 2024 Jun 21.
DOI: 10.1002/alz.13868
Abstrakt: Introduction: The understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic.
Methods: To examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection.
Results: Using quantitative microscopy targeting markers for neurodegeneration and neuroinflammation, as well as fluid and imaging biomarkers, we detailed the progression of misfolded tau spreading and the consequential inflammatory response induced by glial cells.
Discussion: By combining the analysis of several in vivo biomarkers with extensive brain microscopy analysis, we described the initial steps of misfolded tau spreading and neuroinflammation in a monkey model highly translatable to AD patients.
Highlights: Dual tau mutation delivery in the entorhinal cortex induces progressive tau pathology in rhesus macaques. Exogenous human 4R-tau coaptates monkey 3R-tau during transneuronal spread, in a prion-like manner. Neuroinflammatory response is coordinated by microglia and astrocytes in response to tau pathology, with microglia targeting early tau pathology, while astrocytes engaged later in the progression, coincident with neuronal death. Monthly collection of CSF and plasma revealed a profile of changes in several AD core biomarkers, reflective of neurodegeneration and neuroinflammation as early as 1 month after injection.
(© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
Databáze: MEDLINE
Externí odkaz: