Tau, synapse loss and gliosis progress in an Alzheimer's mouse model after amyloid-β immunotherapy.

Autor:	Welikovitch LA; Department of Neurology, Massachusetts General Hospital, Charlestown, MA, 02129, USA.; Harvard Medical School, Boston, MA, 02115, USA., Mate de Gerando A; Department of Neurology, Massachusetts General Hospital, Charlestown, MA, 02129, USA.; Harvard Medical School, Boston, MA, 02115, USA., Khasnavis A; Department of Neurology, Massachusetts General Hospital, Charlestown, MA, 02129, USA., Bhavsar H; Department of Neurology, Massachusetts General Hospital, Charlestown, MA, 02129, USA., Meltzer JC; Department of Neurology, Massachusetts General Hospital, Charlestown, MA, 02129, USA., Buée L; University of Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition Lille F-59000, France., Chibnik LB; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Bussiere T; Research and Development, Biogen, Cambridge, MA 02142, USA., Hyman BT; Department of Neurology, Massachusetts General Hospital, Charlestown, MA, 02129, USA.; Harvard Medical School, Boston, MA, 02115, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Nov 06. Date of Electronic Publication: 2024 Nov 06.
DOI:	10.1093/brain/awae345
Abstrakt:	While preclinical studies assessing drugs for Alzheimer's disease (AD) are conducted in animal models that usually display only one neuropathological feature of AD, patients present with a complex combination of comorbidities and neuropathologies. Importantly, it is well-established that amyloid (Aβ) plaque and tau tangle accumulation interact in a phase-dependent manner, making it difficult to predict how targeting one might influence the other, as well as downstream degeneration. We developed a transgenic mouse model, APP/PS1xTau22, with progressive cortical Aβ deposition and hippocampal tau neurofibrillary inclusions to investigate how both neuropathologies act jointly to bring about neural degeneration, synapse loss, and glial phenotypes. We then assessed whether applying murine chimeric Aducanumab, an anti-amyloid immunotherapy, could impact the synergistic relationship between amyloid and tau. Drug treatment resulted in a ∼70% reduction in Aβ deposition in hippocampal and cortical areas and produced a robust peri-plaque microglial and astrocytic response. Removing amyloid from the brain did not reverse or slow tau pathology or alter synapse loss. Our findings suggest that, once the interaction between amyloid and tau is set in motion, reducing plaque burden by Aβ immunotherapy may stimulate glial responses, but is insufficient to curb degenerative phenotypes in this model. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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