Divergent age-dependent conformational rearrangement within Aβ-amyloid deposits in APP23, APPPS1, and AppNL-F mice

Abstract

Amyloid plaques composed of fibrils of misfolded A{beta} peptides are pathological hallmarks of Alzheimers disease (AD). A{beta} fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potency and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of A{beta} fibrils is valuable to understand disease mechanisms. Here, we investigated how A{beta} fibril morphology in situ differs in A{beta} plaque of different mouse models expressing familial mutations in the A{beta}PP gene. We used a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands, A{beta}-specific antibodies, and different fluorescence microscopy techniques. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL-F have different fibril structures depending on A{beta}PP-processing genotype. Co-staining of A{beta}-specific antibodies showed that individual plaques from APP23 mice, expressing Swedish mutations (NL) have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact A{beta}40 fibrils and the corona region is dominated by diffusely packed A{beta}40 fibrils. On the other hand, the APP knock-in mouse AppNL-F, expressing Iberian mutation (F) along with Swedish mutation has tiny, cored plaques consisting mainly of compact A{beta}42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age dependent polymorph maturation of plaque cores observed for APP23 and APPPS1 mice >12 months, was minuscule in AppNL-F. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules. SignificanceAlzheimers disease (AD) is associated with the formation of deposits in the brain known as A{beta}-amyloid plaques. AD can emerge as a sporadic disease or due to familial mutations in genes encoding for A{beta} precursor and processing proteins. The A{beta}-amyloid found in plaques displays different structures in sporadic AD and in various types of familial AD. We hypothesize that understanding plaque morphology and development is crucial for understanding the initiation and progression of AD. We here compared amyloid structures in three of the most used mouse models of human A{beta}-plaque formation. Our findings suggest significant differences in plaque morphologies and structural maturation processes during aging. Our results emphasize that strain-like differences of A{beta}-amyloids develop as a function of A{beta} precursor protein-processing genetics and age.