Immune senescence in aged APP/PS1 mice
Author:
Abdelmoaty Mai M.1, Yeapuri Pravin1, Machhi Jatin1, Lu Yaman1, Namminga Krista L.1, Kadry Rana2, Lu Eugene1, Bhattarai Shaurav1, Mosley Rodney Lee1ORCID, Gendelman Howard E.1
Affiliation:
1. Department of Pharmacology and Experimental Neuroscience, College of Medicine , University of Nebraska Medical Center , Omaha , NE , USA 2. Department of Cellular and Integrative Physiology , University of Nebraska Medical Center , Omaha , NE , USA
Abstract
Abstract
Objectives
To evaluate the linkage between age and deficits in innate and adaptive immunity which heralds both Alzheimer’s disease (AD) onset and progression. The pathobiological events which underlie and tie these outcomes remain not fully understood.
Methods
To investigate age-dependent immunity in AD, we evaluated innate and adaptive immunity in coordinate studies of regulatory T cell (Treg) function, T cell frequencies, and microglial integrity. These were assessed in blood, peripheral lymphoid tissues, and the hippocampus of transgenic (Tg) amyloid precursor protein/presenilin 1 (APP/PS1) against non-Tg mice. Additionally, immune arrays of hippocampal tissue were performed at 4, 6, 12, and 20 months of age.
Results
APP/PS1 mice showed progressive impairment of Treg immunosuppressive function with age. There was partial restoration of Treg function in 20-month-old mice. Ingenuity pathway analyses of hippocampal tissues were enriched in inflammatory, oxidative, and cellular activation pathways that paralleled advancing age and AD-pathobiology. Operative genes in those pathways included, but were not limited to triggering receptor on myeloid cells 1 (TREM1), T helper type 1 (Th1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Interleukin-17 (IL-17), nitric oxide, acute phase, and T cell receptor signaling pathways were also perturbed. Significant inflammation was observed at 6- and 12-months. However, at 20-months, age associated partial restoration of Treg function reduced inflammatory phenotype.
Conclusions
Impaired Treg function, inflammation and oxidative stress were associated with AD pathology. Age associated partial restoration of Treg function in old mice reduced the hippocampal inflammatory phenotype. Restoring Treg suppressive function can be a therapeutic modality for AD.
Funder
Carol Swarts, MD Emerging Neuroscience Research Laboratory Margaret R. Larson Professorship Frances and Louie Blumkin and Harriet Singer Research Foundations Fogarty International Center
Publisher
Walter de Gruyter GmbH
Reference61 articles.
1. Morrissette, DA, Parachikova, A, Green, KN, LaFerla, FM. Relevance of transgenic mouse models to human Alzheimer disease. J Biol Chem 2009;284:6033–7. https://doi.org/10.1074/jbc.r800030200. 2. Ashe, KH, Zahs, KR. Probing the biology of Alzheimer’s disease in mice. Neuron 2010;66:631–45. https://doi.org/10.1016/j.neuron.2010.04.031. 3. Vitale, P, Salgueiro-Pereira, AR, Lupascu, CA, Willem, M, Migliore, R, Migliore, M, et al.. Analysis of age-dependent alterations in excitability properties of CA1 pyramidal neurons in an APPPS1 model of Alzheimer’s disease. Front Aging Neurosci 2021;13:668948. https://doi.org/10.3389/fnagi.2021.668948. 4. Gong, B, Vitolo, OV, Trinchese, F, Liu, S, Shelanski, M, Arancio, O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 2004;114:1624–34. https://doi.org/10.1172/jci22831. 5. Trinchese, F, Liu, S, Battaglia, F, Walter, S, Mathews, PM, Arancio, O. Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol 2004;55:801–14. https://doi.org/10.1002/ana.20101.
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