Evaluation of the major pathological hallmarks in the humanized APPSAA knock‐in mouse model, in response to drug treatment

Abstract

AbstractBackgroundTo improve clinical translatability of non‐clinical in‐vivo Alzheimer’s disease (AD) models, a humanized APP knock‐in mouse model (APPSAA) was recently created (Xia, D. et al., 2022). This homozygous APP knock‐in model carries a humanized Aβ1‐42 sequence and 3 disease causing mutations (Swedish, Arctic, and Austrian). These modifications lead to increased Aβ42/40 ratios in AD relevant tissues, resulting in an age‐dependent amyloid deposition in the brain. The highest plaque density is found in cortical and hippocampal regions. APPSAA mice also display clear neuroinflammation and an increase in fluid biomarkers of neurodegeneration (NF‐L and total Tau in CSF). Here we assess the value of this model as a tool for non‐clinical efficacy studies of experimental drugs with diverse mechanisms of action to facilitate the development of novel AD therapeutics.MethodAPPSAA mice and WT controls were aged and sacrificed at various time points. In addition, APPSAA mice were treated with drug or vehicle, on a daily basis for 3 months from the age of 3 months onward. The major pathological hallmarks of this model and the treatment effect will be investigated with biochemical and immunohistological assays. Monthly blood sampling will allow the follow up of pathology progression in individual mice by assessing plasma‐based biomarkers. Since APPSAA mice lack an obvious behavioral phenotype, synaptic plasticity will be investigated to serve as a functional readout.ResultThe treatment is well tolerated by the mice in study. Body weights were not altered between compound and vehicle dosing during the first 2 months of the treatment. Data on pathological outcomes and synaptic plasticity are not yet available but will be shared during the presentation.ConclusionA humanized knock‐in model for AD is hypothesized to be a broadly applicable tool to investigate disease‐modifying drugs with diverse modes of actions.