Modeling Alzheimer's disease related phenotypes in the Ts65Dn mouse: impact of age on Aβ, Tau, pTau, NfL, and behavior.

People with DS are highly predisposed to Alzheimer's disease (AD) and demonstrate very similar clinical and pathological features. Ts65Dn mice are widely used and serve as the best-characterized animal model of DS. We undertook studies to characterize age-related changes for AD-relevant markers linked to Aβ, Tau, and phospho-Tau, axonal structure, inflammation, and behavior. We found age related changes in both Ts65Dn and 2N mice. Relative to 2N mice, Ts65Dn mice showed consistent increases in Aβ40, insoluble phospho-Tau, and neurofilament light protein. These changes were correlated with deficits in learning and memory. These data have implications for planning future experiments aimed at preventing disease-related phenotypes and biomarkers. Interventions should be planned to address specific manifestations using treatments and treatment durations adequate to engage targets to prevent the emergence of phenotypes.

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Copyright © 2023 Overk, Fiorini, Babolin, Vukicevic, Morici, Madani, Eligert, Kosco-Vilbois, Roberts, Becker, Pfeifer and Mobley.

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EF, MV, CB, CM, RM, VE, AP, and MK-V are all employees of AC Immune who funded this research. No products of AC Immune were included in this manuscript since only vehicle-treated mice were analyzed. WM serves as a consultant to AC Immune and Acta Pharmaceuticals. WM has grants or contracts from NIH (AG078241, AG070154, AG067035, AG077148, and P01NA092525), Larry L. Hillblom Foundation (2019-A-006-NET), Michael J Fox Foundation (ASAP-020566 and MJFF-020705), Ono Pharma Foundation UCSD 2019–0742, BioSplice Inc., ACI Immune SA, Alzheimer Association DSAD-15-363,207, Cure Alzheimer’s Fund, and Annovis Bio. WM has Royalties or licenses from Curasen Inc. licensed by Stanford (no payment to WM). WM received consulting fees from Samumed, AC Immune SA and Pfizer Inc. WM received support for attending meetings and/or travel from the National Down Syndrome Society, Sanford Health, AC Immune, U Michigan, ASAP Meeting, Sanford Health, Burke-Blythedale Meeting (New York), and ADRD and COBRE meetings (University of Nebraska, Medical Center). WM has patents planned, issued, or pending for the use of gamma-secretase modulators held by UCSD and Harvard. WM received stock or stock options from Annovis Bio (as payment), Cortexyme (as payment), and Alzheon (not as payment). WM received study drug and gift funding to the lab from Annovis Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.