Aβ40 has a subtle effect on Aβ42 protofibril formation, but to a lesser degree than Aβ42 concentration, in Aβ42/Aβ40 mixtures

Abstract

Recent findings suggest that the senile plaques in Alzheimer’s disease may contain soluble amyloid-β peptide (Aβ) fibril precursors along with insoluble fibrils.. These soluble Aβ species, including oligomers and protofibrils, have been well-studied in vitro and are formed via non-covalent self-assembly of Aβ monomers. While both 40- and 42-residue forms of Aβ are observed in the human body, the majority of the Aβ aggregation work has been conducted on Aβ42 or Aβ40 separately, with relatively few investigations of mixtures. In order to study the effect of different combinations of Aβ40 and Aβ42 on protofibril formation, mixtures of either dry solid peptide, or purified Aβ40 and Aβ42 monomer solutions were mixed together and protofibril/monomer distributions were quantified. Increases in the Aβ42/Aβ40 ratio increased protofibril formation but the presence of Aβ40 in the mixed Aβ solutions had a significant negative impact on protofibril formation compared to equivalent solutions of pure Aβ42. Protofibril size was less affected, but β-sheet structure increased with protofibrils formed from higher Aβ42/Aβ40 ratio solutions. Direct measurement of Aβ42/Aβ40 ratios by C-terminal-selective ELISA found very little Aβ40 incorporated into protofibrils. The cumulative data emphasizes the critical importance of Aβ42, yet establishes Aβ40 as a regulator of Aβ42 aggregation.

Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer’s disease neurons

“…Higher concentrations of longer protofibillar aggregates of Aβ, with sizes in the same range as detected in these experiments (40–200 nm), have previously been shown to cause an inflammatory response via TLR4, leading to production of proinflammatory cytokines including TNF ( Paranjape et al , 2013 ; Terrill-Usery et al , 2016 ; Colvin et al , 2017 ). A positive cycle of increased secretion of aggregates leading to increased inflammation and production of TNF and other proinflammatory cytokines could therefore drive increased production of Aβ aggregates in the Alzheimer’s disease brain.…”

Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms

“…By contrast, we observed an opposite trend in the effects of soluble Aβ42 aggregates when monitored by an inflammation assay. Inflammation is driven by pattern recognition receptors, such as toll-like receptors (TLRs) 23,24 . Multiple studies have demonstrated that soluble forms of Aβ interact with the toll-like receptor 4 (TLR4) on microglia cells, resulting in the production of inflammatory cytokines that are thought to contribute to the neuronal damage associated with the progression of AD 24–27 .…”

“…Inflammation is driven by pattern recognition receptors, such as toll-like receptors (TLRs) 23,24 . Multiple studies have demonstrated that soluble forms of Aβ interact with the toll-like receptor 4 (TLR4) on microglia cells, resulting in the production of inflammatory cytokines that are thought to contribute to the neuronal damage associated with the progression of AD 24–27 . To study and quantify the inflammation induced in cells by the Aβ42 protein aggregates, we monitored the levels of secreted tumour necrosis factor alpha (TNF-ɑ), a pro-inflammatory cytokine, using an enzyme-linked immunosorbent assay (ELISA) assay 28 (Fig.…”

Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer’s disease progression

“…Additionally, these data are also in agreement with previous reports on synthetic Aβ aggregates, which cannot undergo post-translational modifications. It was found that Aβ aggregates greater than 100 nm formed in artificial CSF can trigger an inflammatory response in microglial cells that can be blocked by an Aβ N-terminal region recognising antibody [8, 31, 42]. We also recently reported results that small aggregates of Aβ42 which form during the early stages of aggregation are more potent at membrane permeabilisation, whereas protofilament aggregates of similar length to the aggregates detected in CSF with height of 0.4–1 nm, which form at later stages of aggregation, are more effective at inducing inflammatory response in murine glial cells via TLR4 receptor [10].…”