Noor A, Zafar S, Shafiq M, Younas N, Siegert A, Mann FA, Kruss S, Schmitz M, Dihazi H, Ferrer I, Zerr I

The molecular determinants of atypical clinical variants of Alzheimer's disease, including the recently discovered rapidly progressive Alzheimer's disease (rpAD), are unknown to date. Fibrilization of the amyloid-? (A?) peptide is the most frequently studied candidate in this context. The A? peptide can exist as multiple proteoforms that vary in their ...

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post-translational processing, amyloidogenesis, and toxicity. The current study was designed to identify these variations in Alzheimer's disease patients exhibiting classical (sAD) and rapid progression, with the primary aim of establishing if these variants may constitute strains that underlie the phenotypic variability of Alzheimer's disease. We employed two-dimensional polyacrylamide gel electrophoresis and MALDI-ToF mass spectrometry to validate and identify the A? proteoforms extracted from targeted brain tissues. The biophysical analysis was conducted using RT-QuIC assay, confocal microscopy, and atomic force microscopy. Interactome analysis was performed by co-immunoprecipitation. We present a signature of 33 distinct pathophysiological proteoforms, including the commonly targeted A?40, A?42, A?4-42, A?11-42, and provide insight into their synthesis and quantities. Furthermore, we have validated the presence of highly hydrophobic A? seeds in rpAD brains that seeded reactions at a slower pace in comparison to typical Alzheimer's disease. In vitro and in vivo analyses also verified variations in the molecular pathways modulated by brain-derived A?. These variations in the presence, synthesis, folding, and interactions of A? among sAD and rpAD brains constitute important points of intervention. Further validation of reported targets and mechanisms will aid in the diagnosis of and therapy for Alzheimer's disease.

Date: Jan. 01, 2022

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