Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer’s disease related oligomers

Abstract

The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers.

Formaldehyde‐Crosslinked Nontoxic Aβ Monomers to Form Toxic Aβ Dimers and Aggregates: Pathogenicity and Therapeutic Perspectives

“…In 2008, a synthetic peptide RGKLVFFGR-NH2 (OR2), which contained the Aβ amino acid sequence (KLVFF) from the binding region responsible for Aβ self-association (residues [16][17][18][19][20], was shown to inhibit Aβ oligomerization and aggregation in vitro, [175] reduce Aβ toxicity in the cultured human SH-SY5Y cells, [176] and reverse Aβ-related pathological characteristics in APPswe/PS1ΔE9 transgenic mice. [177] In 2020 year, OR2 was found to bind with Aβ dimers (Dimer/OR2) [178] (Figure 4b), and a result, directly disturbed Aβ oligomerization and fibrillation. Notably, other synthetic peptides, such as: RI-OR2-TA, [176] Lysspecific molecular tweezer, [178] L-histidyl-L-alanyl-Lhistidine, [148,179] Ac-HAEE-NH2, andAc-RADD-NH2, [180] have been found to act as the ligands of Aβ dimers to disassemble Aβ aggregation in vitro.…”

“…[177] In 2020 year, OR2 was found to bind with Aβ dimers (Dimer/OR2) [178] (Figure 4b), and a result, directly disturbed Aβ oligomerization and fibrillation. Notably, other synthetic peptides, such as: RI-OR2-TA, [176] Lysspecific molecular tweezer, [178] L-histidyl-L-alanyl-Lhistidine, [148,179] Ac-HAEE-NH2, andAc-RADD-NH2, [180] have been found to act as the ligands of Aβ dimers to disassemble Aβ aggregation in vitro. The positive clinical therapeutic effects of these interfering peptides are promising.…”

Wie kleine Amyloid-β-Peptide zum großen Problem im Gehirn werden können

“…3). Vergleiche mit in vacuo-Simulationen der Molaküldynamik (MD) von Aβ 42 -Strukturmodellen zeigten zudem eine hohe Übereinstimmung mit den experimentellen CCS der Aggregation analog zu einer Perlenkette sowie zu einem Reißverschluss [8]. Zudem konnte die Analyse der vorliegenden Sekundärstrukturelemente in Abhängigkeit von der Oligomergröße eine erhöhte Ausbildung von β-Faltblatt strukturelementen im Fall der Reißverschlussaggregation bestätigt werden.…”

“…Um die Aggregation und die postulierte Interaktion weiterer Monomeruntereinheiten zu validieren, wurden zusätzliche Experimente in Gegenwart der Aggregationsinhibitoren CLR01 sowie OR2 durchgeführt, die jeweils die Ausbildung von Fibrillen unterbinden und einen niederoligomeren Zustand gewährleisten sollen [8]. Während es sich bei CLR01 um einen Lysin-bzw.…”

“…Um diese Aggregation für die Alzheimerrelevanten Peptide genauer zu untersuchen, haben wir für Aβ 42 die Phase der frühen Oligomerisierung mittels LILBID-MS näher charakterisiert, wobei sich binnen 200 Minuten Oligomere bis hin zum 12-mer nachweisen lassen[8]. TEM-Aufnahmen nach 48 Stunden bestätigen, dass diese zur Bildung von definierten Fibrillen führten (Abb.…”