Delineating amyloid peptide signatures among heterogenous plaque population in Alzheimer’s Disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disorder affecting nearly 12% of individuals older than 65 years. The disease poses an immense societal challenge and personal suffering, particularly as there were still no curative treatments as the pathogenic mechanisms of AD remain elusive. One of the main challenge would be to understand the chemical basis of heterogeneity involved in the formation of variety of plaque polymorphs. These plaques are known to be extracellular deposits of amyloid beta (AB) peptide. In this study we aim to investigate the chemical nature of structuraly diverse plaque polymorphs in patient samples with sporadic AD, familial AD and Cognitively unimpaired pathological ageing.MethodWe employed a novel chemical imaging strategy combining microscopy with matrix assisted laser desorption/ioninsation ‐ mass spectrometry imaging (MALDI‐MSI) to delineate AB signatures of heterogenous plaque polymorphs. These plaques are then grouped into sAD‐diffused plaques (DP), sAD‐cored plaques (CP), sAD coarse grain plaques (sAD‐CG), CU‐AP diffused plaques(DP of CU‐AP), fAD cored plaques (fAD‐CP) and fAD coarse grain plaques (fAD‐CG) along with amyloid vasculature from sAD and fAD based on the high resolution hyperspectral microscopy images combined with multivariate image analysis performed on MALDI‐MSI data. These plaques are then investigated for differences in the AB signatures.ResultAβ1‐40 is more abundant in more compact plaques like CG and CP in comparison to DP and DP of CU‐AP. Aβ3pE‐40 in less aggregated diffused plaques of CU‐AP than cored plaques of sAD.ConclusionThis study provides neurochemical information of the amyloid plaque polymorphs crucial for the development of a biomarker . Our data suggests Aβ1‐40 and 3pE depositions are critical in plaque maturation . fAD plaques are more compact than in sAD, larger extend of Aβ1‐40/1‐42. We also present the chemical characterization of coarse grain plaques for the first time. Similarities of CG to CAA point towards vascular involvement in the formation of coarse grain plaques