Transgenic amyloid precursor protein mouse models of amyloidosis. Incomplete models for Alzheimer's disease but effective predictors of anti-amyloid therapies

Abstract

Introduction: Amyloid precursor protein (APP) transgenic mice are models of Alzheimer's disease (AD) amyloidosis, not all of AD. Diffuse, compacted, and vascular deposits in APP mice mimic those found in AD cases.

Methods: Most interventional studies in APP mice start treatment early in the process of amyloid deposition, consistent with a prevention treatment regimen. Most clinical trials treat patients with established amyloid deposits in a therapeutic treatment regimen.

Results: The first treatment to reduce amyloid and cognitive impairment in mice was immunotherapy. The APP mouse models not only predicted efficacy, but presaged the vascular leakage called ARIA. The recent immunotherapy clinical trials that removed amyloid and slowed cognitive decline confirms the utility of these early APP models when used in therapeutic designs.

Discussion: New mouse models of AD pathologies will add to the research armamentarium, but the early models have accurately predicted responses to amyloid therapies in humans.

Keywords: ARIA; BACE inhibitors; amyloid; immunotherapy; mouse models; prevention studies; therapeutic studies; transgenic mice.

FIGURE 1

Comparison of prevention study design with therapeutic study design and human clinical trials. In preclinical prevention designs, interventions are administered either prior to the onset of amyloid deposition or in the early phases. Mice are often tested behaviorally at a time point shortly after memory deficits are apparent. Tissues are collected shortly after behavioral testing. In a therapeutic treatment design, mice are matured to an age when amyloid deposits are well established before treatment starts. Mice are then tested behaviorally and tissues collected. In a clinical trial, both amyloid and tau have been present for years, and participants are tested for memory loss and presence of pathology before interventions are administered. After 1 to 2 years participants are re‐tested and pathology and biomarkers measured in placebo and treatment groups. No tissue is collected until later at autopsy. Very few drugs have been tested in mouse therapeutic trials before human clinical trials. Created with Biorender.