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

Biomedicines - Tập 10 Số 11 - Trang 2753
Nicolas Papadopoulos1,2, Núria Suelves3, Florian Perrin4, Devkee M. Vadukul5, Céline Vrancx6,7, Stefan N. Constantinescu1,8,2,9, Pascal Kienlen‐Campard3
1Ludwig Institute for Cancer Research Brussels, 1348 Brussels, Belgium
2SIGN Unit, de Duve Institute, UCLouvain, 1200 Brussels, Belgium
3Aging and Dementia Research Group, Cellular and Molecular (CEMO) Division, Institute of Neuroscience, UCLouvain, 1200 Brussels, Belgium
4Memory Disorders Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
5Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London SW7 2BX, UK
6Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium
7Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research, KU Leuven, 3000 Leuven, Belgium
8Nuffield Department of Medicine, Ludwig Institute for Cancer Research, Oxford University, Oxford OX1 2JD, UK
9Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1300 Wavre, Belgium

Tóm tắt

Most neurodegenerative diseases have the characteristics of protein folding disorders, 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 diseases. It is characterized by two types of lesions: neurofibrillary tangles (NFTs) composed of tau proteins and senile plaques, formed essentially of amyloid peptides (Aβ). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate Aβ deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify Aβ production, and to understand the processes leading to the formation of different Aβ aggregates, e.g., fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and Aβ production essentially by regulating membrane protein dimerization, and subsequently Aβ 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 is critical to better decipher the patterns switching APP protein conformation from physiological to pathological and improve our understanding of the mechanisms underpinning the formation of amyloid fibrils that devastate neuronal functions.

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