Comparative Analysis of Amyloid-β Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer's Disease Brains

We have undertaken an integrated chemical and morphological comparison of the amyloid-β (Aβ) molecules and the amyloid plaques present in the brains of APP23 transgenic (tg) mice and human Alzheimer's disease (AD) patients. Despite an apparent overall structural resemblance to AD pathology, our detailed chemical analyses revealed that although the amyloid plaques characteristic of AD contain cores that are highly resistant to chemical and physical disruption, the tg mice produced amyloid cores that were completely soluble in buffers containing SDS. Aβ chemical alterations account for the extreme stability of AD plaque core amyloid. The corresponding lack of post-translational modifications such as N-terminal degradation, isomerization, racemization, pyroglutamyl formation, oxidation, and covalently linked dimers in tg mouse Aβ provides an explanation for the differences in solubility between human AD and the APP23 tg mouse plaques. We hypothesize either that insufficient time is available for Aβ structural modifications or that the complex species-specific environment of the human disease is not precisely replicated in the tg mice. The appraisal of therapeutic agents or protocols in these animal models must be judged in the context of the lack of complete equivalence between the transgenic mouse plaques and the human AD lesions.