Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates
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 dise...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/10/11/2753 |
| _version_ | 1797468968544370688 |
|---|---|
| author | Nicolas Papadopoulos Nuria Suelves Florian Perrin Devkee M. Vadukul Céline Vrancx Stefan N. Constantinescu Pascal Kienlen-Campard |
| author_facet | Nicolas Papadopoulos Nuria Suelves Florian Perrin Devkee M. Vadukul Céline Vrancx Stefan N. Constantinescu Pascal Kienlen-Campard |
| author_sort | Nicolas Papadopoulos |
| collection | DOAJ |
| description | 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 (<i>APP</i>) 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 <i>APP</i> 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 <i>APP</i> conformation to trigger the transition to the amyloid pathology. This concept is critical to better decipher the patterns switching <i>APP</i> protein conformation from physiological to pathological and improve our understanding of the mechanisms underpinning the formation of amyloid fibrils that devastate neuronal functions. |
| first_indexed | 2024-03-09T19:14:50Z |
| format | Article |
| id | doaj.art-0eaccee654984de88c7b6d0588f1e379 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T19:14:50Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-0eaccee654984de88c7b6d0588f1e3792023-11-24T03:50:10ZengMDPI AGBiomedicines2227-90592022-10-011011275310.3390/biomedicines10112753Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid AggregatesNicolas Papadopoulos0Nuria Suelves1Florian Perrin2Devkee M. Vadukul3Céline Vrancx4Stefan N. Constantinescu5Pascal Kienlen-Campard6SIGN Unit, de Duve Institute, UCLouvain, 1200 Brussels, BelgiumAging and Dementia Research Group, Cellular and Molecular (CEMO) Division, Institute of Neuroscience, UCLouvain, 1200 Brussels, BelgiumMemory Disorders Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London SW7 2BX, UKLaboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research, KU Leuven, 3000 Leuven, BelgiumSIGN Unit, de Duve Institute, UCLouvain, 1200 Brussels, BelgiumAging and Dementia Research Group, Cellular and Molecular (CEMO) Division, Institute of Neuroscience, UCLouvain, 1200 Brussels, BelgiumMost 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 (<i>APP</i>) 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 <i>APP</i> 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 <i>APP</i> conformation to trigger the transition to the amyloid pathology. This concept is critical to better decipher the patterns switching <i>APP</i> protein conformation from physiological to pathological and improve our understanding of the mechanisms underpinning the formation of amyloid fibrils that devastate neuronal functions.https://www.mdpi.com/2227-9059/10/11/2753Alzheimer’s diseaseAmyloid Precursor Proteinamyloid beta<i>APP</i>-C99dimerizationorientations |
| spellingShingle | Nicolas Papadopoulos Nuria Suelves Florian Perrin Devkee M. Vadukul Céline Vrancx Stefan N. Constantinescu Pascal Kienlen-Campard Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates Biomedicines Alzheimer’s disease Amyloid Precursor Protein amyloid beta <i>APP</i>-C99 dimerization orientations |
| title | Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates |
| title_full | Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates |
| title_fullStr | Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates |
| title_full_unstemmed | Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates |
| title_short | Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates |
| title_sort | structural determinant of β amyloid formation from transmembrane protein dimerization to β amyloid aggregates |
| topic | Alzheimer’s disease Amyloid Precursor Protein amyloid beta <i>APP</i>-C99 dimerization orientations |
| url | https://www.mdpi.com/2227-9059/10/11/2753 |
| work_keys_str_mv | AT nicolaspapadopoulos structuraldeterminantofbamyloidformationfromtransmembraneproteindimerizationtobamyloidaggregates AT nuriasuelves structuraldeterminantofbamyloidformationfromtransmembraneproteindimerizationtobamyloidaggregates AT florianperrin structuraldeterminantofbamyloidformationfromtransmembraneproteindimerizationtobamyloidaggregates AT devkeemvadukul structuraldeterminantofbamyloidformationfromtransmembraneproteindimerizationtobamyloidaggregates AT celinevrancx structuraldeterminantofbamyloidformationfromtransmembraneproteindimerizationtobamyloidaggregates AT stefannconstantinescu structuraldeterminantofbamyloidformationfromtransmembraneproteindimerizationtobamyloidaggregates AT pascalkienlencampard structuraldeterminantofbamyloidformationfromtransmembraneproteindimerizationtobamyloidaggregates |