Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates

• DOI: 10.20944/preprints202210.0056.v1
• Publication Date: 2022-10-06T13:07:47Z
• Authors: Nicolas Papadopoulos; Nuria Suelves; Florian Perrin; Devkee M. Vadukul; Céline Vrancx; Stefan N. Constan...; Pascal Kienlen-Ca...
• Keywords: life_sciences_other; 0301 basic medicine; Biochemistry & Molecular Biology; GAMMA-SECRETASE; QH301-705.5; Medicine (miscellaneous); CLEAVING ENZYME; Genetics and Molecular Biology; Review; Research & Experimental Medicine; APOLIPOPROTEIN-E; oligomerization; neuroscience; 03 medical and health sciences; orientations; GXXXG MOTIF; <i>APP</i>-C99; Pharmacology & Pharmacy; Biology (General); A-BETA; neuropathology; C-TERMINAL DOMAIN; Science & Technology; dimerization; PRECURSOR PROTEIN; aggregation; APP-C99; Alzheimer's disease; 3. Good health; ALZHEIMERS-DISEASE; APP DIMERIZATION; BINDING-SITE; amyloid beta; Medicine, Research & Experimental; General Biochemistry; Amyloid Precursor Protein; Life Sciences & Biomedicine; Alzheimer’s disease

Most neurodegenerative diseases have the characteristics of proteinopathies, i.e. they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer's disease is one of these proteinopathies. It is characterized by two lesions, neurofibrillary tangles (NFTs) and senile plaques, formed essentially of amyloid peptides (A&beta;). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate A&beta; deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify A&beta; production, and to understand the processes leading to the formation of different A&beta; aggregates; e.g. fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and A&beta; production essentially by regulating membrane dimerization, and subsequently A&beta; aggregation processes. The distinct properties of these motifs and the cellular context regulate the APP conformation to trigger the transition to the amyloid pathology. This concept can be transposed to the study of other proteinopathies, providing a framework for improving our understanding of these mechanisms that devastate neuronal functions.