Comparative analysis of amyloid-beta chemical structure and amyloid plaquemorphology of transgenic mouse and Alzheimer's disease brains

We have undertaken an integrated chemical and morphological comparison of t he amyloid-beta (A beta) molecules and the amyloid plaques present in the b rains of APP23 transgenic (tg) mice and human Alzheimer's disease (AD) pati ents. Despite an apparent overall structural resemblance to AD pathology, o ur detailed chemical analyses revealed that although the amyloid plaques ch aracteristic of AD contain cores that are highly resistant to chemical and physical disruption, the tg mice produced amyloid cores that were completel y soluble in buffers containing SDS, A beta chemical alterations account fo r the extreme stability of AD plaque core amyloid. The corresponding lack o f post-translational modifications such as N-terminal degradation, isomeriz ation, racemization, pyroglutamyl formation, oxidation, and covalently link ed dimers in tg mouse A beta 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 A beta structural modificat ions or that the complex species-specific environment of the human disease is not precisely replicated in the tg mice. The appraisal of therapeutic ag ents or protocols in these animal models must be judged in the context of t he lack of complete equivalence between the transgenic mouse plaques and th e human AD lesions.