Correlative Chemical Imaging Identifies Amyloid Peptide Signatures of Neuritic Plaques and Dystrophy in Human Sporadic Alzheimer's Disease.

ABSTRACT

Objective: Alzheimer's disease (AD) is the most common neurodegenerative disease. The predominantly sporadic form of AD is age-related, but the underlying pathogenic mechanisms remain not fully understood. Current efforts to combat the disease focus on the main pathological hallmarks, in particular beta-amyloid (Aß) plaque pathology. According to the amyloid cascade hypothesis, Aß is the critical early initiator of AD pathogenesis. Plaque pathology is very heterogeneous, where a subset of plaques, neuritic plaques (NPs), are considered most neurotoxic rendering their in-depth characterization essential to understand Aß pathogenicity. Methods: To delineate the chemical traits specific to NP types, we investigated senile Aß pathology in the postmortem, human sporadic AD brain using advanced correlative biochemical imaging based on immunofluorescence (IF) microscopy and mass spectrometry imaging (MSI). Results: Immunostaining-guided MSI identified distinct Aß signatures of NPs characterized by increased Aß1-42(ox) and Aß2-42. Moreover, correlation with a marker of dystrophy (reticulon 3 [RTN3]) identified key Aß species that both delineate NPs and display association with neuritic dystrophy. Conclusion: Together, these correlative imaging data shed light on the complex biochemical architecture of NPs and associated dystrophic neurites. These in turn are obvious targets for disease-modifying treatment strategies, as well as novel biomarkers of Aß pathogenicity.