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

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 (A beta) plaque pathology. According to the amyloid cascade hypothesis, A beta 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 A beta pathogenicity.Methods: To delineate the chemical traits specific to NP types, we investigated senile A beta 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 A beta signatures of NPs characterized by increased A beta 1-42(ox) and A beta 2-42. Moreover, correlation with a marker of dystrophy (reticulon 3 [RTN3]) identified key A beta 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 A beta pathogenicity.