Chemical imaging signatures delineate heterogeneous amyloid plaque populations across the Alzheimers disease spectrum

Abstract

Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimers disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic A{beta} plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated A{beta} compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct A{beta} signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of A{beta}x-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more A{beta}x-40 and less A{beta}x-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the A{beta} peptide content in coarse grain plaques resembled that of vascular A{beta} deposits (CAA) though with relatively higher levels of A{beta}1-42 and pyroglutamated A{beta}x-40 and A{beta}x-42 species in coarse grain plaques. This is the first of its kind study on spatial in situ biochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.