Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer’s Disease

Abstract

The amyloid pathology characteristic of Alzheimer’s disease (AD) can be broadly classified as either fibrillary amyloid or diffuse amyloid. Fibrillary amyloid is found in cored-neuritic deposits, fibrillar deposits, and vascular deposits, and binds strongly to the amyloid revealing dyes Thioflavin-S or Congo Red. Diffuse amyloid can appear as wispy dispersed deposits or compact tufted deposits dispersed in neuropil, and binds amyloid dyes weakly if at all. In AD brains, both types of pathology are detected. Homogenates from AD brains, or the brains of transgenic mice modeling AD-amyloidosis, have been used to seed pathology in vulnerable host transgenic models. These studies suggest that pathologies may arise from distinct conformers or strains of misfolded Aβ, similar to propagating prions. Using Aβ strains sourced from four different AD-amyloidosis models, we injected pathological seeds into the brains of newborn mice from three different transgenic hosts with distinctive Aβ pathologies. Two of the seeding sources were from mice that primarily develop cored-neuritic Aβ deposits (cored strain) while the other two seeding sources were from mice that develop diffuse Aβ deposits (diffuse strain). These seeds were injected into host APP mice in which the resident strain was either diffuse or cored-neuritic pathology. Seeding-homogenates were injected into the brains of newborn mice to initiate propagation as early as possible. Depending upon the level of transgene expression in the host, we show that the injected strains of misfolded Aβ from the seeding homogenate were able to outcompete the resident strain of the APP host model. In serial passaging experiments, it appeared that the diffuse strain was more easily propagated than the cored strain. Collectively, our studies align with the idea that different types of Aβ pathology in AD brains arise from different populations of Aβ conformers that compete to populate the brain.