Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Article type: Research Article

Authors: Liu, Peng^{a; b} | Reichl, John H.^{a; b} | Rao, Eshaan R.^{b; e} | McNellis, Brittany M.^{b; e} | Huang, Eric S.^{a; b} | Hemmy, Laura S.^{c; f} | Forster, Colleen L.^{b; d} | Kuskowski, Michael A.^c | Borchelt, David R.^g | Vassar, Robert^h | Ashe, Karen H.^{a; b; e; f} | Zahs, Kathleen R.^{a; b; *}

Affiliations: [a] Department of Neurology, University of Minnesota, Minneapolis, MN, USA | [b] N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN, USA | [c] Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA | [d] UMN Academic Health Center Biological Materials Procurement Network, University of Minnesota, Minneapolis, MN, USA | [e] Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA | [f] GRECC, VA Medical Center, Minneapolis, MN, USA | [g] Department of Neuroscience, University of Florida, Gainesville, FL, USA | [h] Department of Cellular and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Correspondence: [*] Correspondence to: Kathleen R. Zahs, N. Bud Grossman Center for Memory Research and Care, 5-184 Wallin Medical Biosciences Building, 2101 6th Street SE, Minneapolis, MN 55455, USA. Tel.: +1 612 624 9985; Fax: +1 612 626 2639; E-mail: [email protected].

Abstract: There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer’s disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21–24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.

Keywords: Alzheimer’s disease, amyloid plaque, amyloid-β protein precursor, plaque burden, plaque size, Thioflavin S, transgenic mouse

DOI: 10.3233/JAD-161027

Journal: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 743-761, 2017