Paradoxical attenuation of early amyloid-induced cognitive impairment and synaptic plasticity in an aged APP/Tau bigenic rat model.

Autor: Emmerson JT; Department of Pharmacology & Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler Room 1210, Montreal, H3G 1Y6, Canada., Do Carmo S; Department of Pharmacology & Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler Room 1210, Montreal, H3G 1Y6, Canada., Lavagna A; Department of Pharmacology & Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler Room 1210, Montreal, H3G 1Y6, Canada., Huang C; Department of Pharmacology & Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler Room 1210, Montreal, H3G 1Y6, Canada., Wong TP; Department of Psychiatry, McGill University, Montreal, H4H 1R3, Canada., Martinez-Trujillo JC; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Robarts Research Institute and Brain and Mind Institute, University of Western Ontario Lawson Health Research InstituteOxford University, Oxford, ON, N6A 5B7, Canada.; Lawson Health Research Institute, Oxford, ON, N6A 5B7, Canada., Cuello AC; Department of Pharmacology & Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler Room 1210, Montreal, H3G 1Y6, Canada. claudio.cuello@mcgill.ca.; Department of Pharmacology, Oxford University, London, ON, N6A 5B7, UK. claudio.cuello@mcgill.ca.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2024 Dec 20; Vol. 12 (1), pp. 193. Date of Electronic Publication: 2024 Dec 20.
DOI: 10.1186/s40478-024-01901-0
Abstrakt: The combination of amyloid beta and tau pathologies leads to tau-mediated neurodegeneration in Alzheimer's disease. However, the relative contributions of amyloid beta and tau peptide accumulation to the manifestation of the pathological phenotype in the early stages, before the overt deposition of plaques and tangles, are still unclear. We investigated the longitudinal pathological effects of combining human-like amyloidosis and tauopathy in a novel transgenic rat model, coded McGill-R-APPxhTau. We compared the effects of individual and combined amyloidosis and tauopathy in transgenic rats by assessing the spatiotemporal progression of Alzheimer's-like amyloid and tau pathologies using biochemical and immunohistochemical methods. Extensive behavioral testing for learning and memory was also conducted to evaluate cognitive decline. Additionally, we investigated brain inflammation, neuronal cell loss, as well as synaptic plasticity through acute brain slice electrophysiological recordings and Western blotting. Evaluation of Alzheimer's-like amyloidosis and tauopathy, at the initial stages, unexpectedly revealed that the combination of amyloid pathology with the initial increment in phosphorylated tau exerted a paradoxical corrective effect on amyloid-induced cognitive impairments and led to a compensatory-like restoration of synaptic plasticity as revealed by electrophysiological evidence, compared to monogenic transgenic rats with amyloidosis or tauopathy. We discovered elevated CREB phosphorylation and increased expression of postsynaptic proteins as a tentative explanation for the improved hippocampal synaptic plasticity. However, this tau-induced protective effect on synaptic function was transient. As anticipated, at more advanced stages, the APPxhTau bigenic rats exhibited aggravated tau and amyloid pathologies, cognitive decline, increased neuroinflammation, and tau-driven neuronal loss compared to monogenic rat models of Alzheimer's-like amyloid and tau pathologies. The present findings propose that the early accumulation of phosphorylated tau may have a transient protective impact on the evolving amyloid pathology-derived synaptic impairments.
Competing Interests: Declarations. Ethics approval and consent to participate: The use of animals for this study was approved by the McGill Animal Care Committee under the guidelines of the Canadian Council on Animal Care (CCAC). Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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