Modelling of the development and response to amyloid‐β accumulation in the context of trisomy21 in the rodent brain

Abstract

AbstractBackgroundIndividuals who have Down syndrome (DS), a genetic condition caused by having three copies of chromosome 21, frequently develop early‐onset Alzheimer’s disease (AD). This is caused by the additional copy of the APP gene, located on chromosome 21, which leads to a raised abundance of amyloid‐β. However, significant evidence demonstrates that the additional copy of other genes on the chromosome modifies the accumulation and response to amyloid‐β. Here we present a series of rodent preclinical models of AD‐DS, which we use to investigate this biology and can be used to test potential therapeutic approaches.MethodsWe previously crossed mouse models of DS with the AppNL‐F model of amyloid‐β accumulation; demonstrating that three copies of a region of chromosome 21 containing 38 genes is sufficient to reduce the accumulation of amyloid‐β. Here we present new data from a cross of the Dp1Tyb DS mouse model with an App gene knock‐out (to normalise the number of copies of this gene) and novel DS‐AD rodent models in which the endogenous App gene has been partially humanized (Dup(Rno11)‐APP‐H3 and Ts68Yah) compared with DS model controls (Dup(Rno11) and Ts66Yah). Brain material from these models at a range of ages was analyzed by western blot, biochemical fractionation and MSD assay, and immunohistology to study APP processing and amyloid‐β accumulation. We used MSD assay and immunofluorescence to study the response to accumulating amyloid‐β with a focus on the response of microglia, neuroinflammation and break‐down of the blood‐brain barrier.ResultsOur data indicate that three copies of App contribute to altered microglia biology in the Dp1Tyb mouse model of DS and that partial humanization of the App gene in DS rodent models leads to alterations in the processing of APP, and results in raised levels of human amyloid‐β in the brain.ConclusionThese new model systems of DS‐AD amyloid‐β biology can be used to better understand the early development of AD in people who have DS and to test the safety and efficacy of new therapies for this important group of individuals who are at extremely high risk of developing early onset dementia.