Delayed Formation and Prolonged Lifetime of Myddosomes Triggered by Amyloid-Beta Aggregates Compared to Lipopolysaccharide

Core Concepts

Amyloid-beta aggregates trigger the formation of larger and longer-lived Myddosomes compared to the canonical TLR4 agonist lipopolysaccharide, leading to less efficient TLR4 signaling.

Abstract

The study investigated the formation and dynamics of the Myddosome signaling complex in macrophages in response to triggering by the TLR4 agonists lipopolysaccharide (LPS) and sonicated amyloid-beta (Aβ) fibrils. Using local delivery of the agonists via a nanopipette and 3D light sheet imaging, the authors found several key differences between the Myddosomes formed by the two agonists:

Myddosomes formed more rapidly in response to LPS (80 seconds) compared to sonicated Aβ fibrils (372 seconds).
The mean lifetime of Myddosomes was shorter when triggered by LPS (170 seconds) compared to Aβ fibrils (220 seconds).
Super-resolution imaging revealed that Myddosomes formed in response to Aβ fibrils were larger on average than those formed by LPS, especially at early time points.
The Myddosomes formed in response to Aβ fibrils also showed a higher proportion of larger, less circular complexes compared to the LPS-triggered Myddosomes.

The authors propose that the multivalent nature of Aβ fibrils, allowing them to bind multiple TLR4 receptors simultaneously, leads to the formation of larger Myddosomes that take longer to assemble and disassemble. This may explain the less efficient TLR4 signaling observed in response to Aβ aggregates compared to the canonical agonist LPS. The structural diversity of Myddosomes formed by different agonists may be an important factor in determining the downstream signaling outcomes.

Stats

The first Myddosome formed 80 seconds after LPS delivery, compared to 372 seconds for sonicated Aβ fibrils.
The mean lifetime of Myddosomes was 170 seconds for LPS and 220 seconds for sonicated Aβ fibrils.

Quotes

"Myddosomes formed more rapidly after LPS than in response to sonicated Aβ 1-42 fibrils (80 seconds vs 372 seconds)."
"The mean lifetimes of the Myddosomes was also shorter when triggered by LPS compared to sonicated Aβ fibrils (170 and 220 s) respectively."
"Myddosomes formed in response to Aβ fibrils were larger on average than those formed by LPS, especially at early time points."

Key Insights Distilled From

The delayed kinetics of Myddosome formation explains why Aβ aggregates trigger TLR4 less efficiently than LPS

by Li,B., Sures... at www.biorxiv.org 09-29-2023

https://www.biorxiv.org/content/10.1101/2023.09.28.559977v2

Deeper Inquiries

How do the structural differences in Myddosomes formed by LPS and Aβ fibrils impact their signaling competency and downstream effects?

The structural differences in Myddosomes formed by LPS and Aβ fibrils play a crucial role in determining their signaling competency and downstream effects. Myddosomes are key innate immune signaling platforms that coordinate the production of pro-inflammatory cytokines. When triggered by LPS, Myddosomes form more rapidly and are shorter-lived compared to Myddosomes triggered by Aβ fibrils. This difference in kinetics is significant as it affects the efficiency and magnitude of the downstream signaling response.
In the case of Aβ fibrils, the multivalency of the aggregates leads to the formation of larger Myddosomes that form more slowly and take longer to disassemble. These larger Myddosomes triggered by Aβ fibrils may have altered structural properties that impact their signaling competency. The prolonged lifetime of Aβ-triggered Myddosomes allows for sustained cytokine production, leading to a distinct pattern of TLR4 signaling compared to LPS. The size and shape distribution of the Myddosomes also vary between LPS and Aβ fibrils, with Aβ-triggered Myddosomes being larger and potentially more complex in structure.
Overall, the structural differences in Myddosomes formed by LPS and Aβ fibrils influence their signaling efficiency, duration, and downstream effects. Understanding these structural variations is essential for elucidating the mechanisms underlying the differential immune responses triggered by different agonists.

How do the structural differences in Myddosomes formed by LPS and Aβ fibrils impact their signaling competency and downstream effects?

Several factors beyond multivalency may contribute to the delayed and prolonged Myddosome formation observed with Aβ fibrils compared to LPS. While multivalency plays a significant role in the formation of larger Myddosomes triggered by Aβ fibrils, other factors can also influence the kinetics and dynamics of Myddosome assembly and disassembly.
One potential factor is the affinity of Aβ fibrils for TLR4 compared to LPS. The binding affinity of the agonist to TLR4 can affect the speed of Myddosome formation, as higher affinity interactions may lead to faster complex assembly. Additionally, the size and conformation of the Aβ fibrils themselves may impact the rate of receptor binding and subsequent signaling cascade activation.
Furthermore, the presence of co-receptors or accessory proteins that interact with TLR4 and modulate its signaling pathway could also contribute to the differences in Myddosome dynamics. These co-receptors may influence the stability and activity of the Myddosome complex, leading to variations in signaling efficiency and downstream effects.
Cellular factors such as membrane composition, lipid rafts, and cytoskeletal elements could also play a role in modulating Myddosome formation kinetics. Changes in the cellular microenvironment induced by Aβ fibrils may affect the recruitment and assembly of signaling components, leading to altered Myddosome dynamics.
Overall, a combination of factors, including agonist affinity, structural properties of the agonists, presence of co-receptors, and cellular microenvironment, may contribute to the delayed and prolonged Myddosome formation observed with Aβ fibrils compared to LPS.

Could the insights from this study on Myddosome dynamics be applied to understand TLR4 signaling in response to other protein aggregates implicated in neurodegenerative diseases?

The insights gained from studying Myddosome dynamics in response to Aβ fibrils and LPS could be valuable for understanding TLR4 signaling in response to other protein aggregates implicated in neurodegenerative diseases. Protein aggregates such as tau and α-synuclein, which are associated with neurodegenerative disorders like Alzheimer's and Parkinson's disease, also interact with TLR4 and trigger inflammatory responses.
By applying the knowledge obtained from the study of Myddosome formation kinetics and structural differences in response to Aβ fibrils and LPS, researchers can investigate how other protein aggregates modulate TLR4 signaling. The principles of multivalency, Myddosome size, shape distribution, and signaling competency observed in the context of Aβ fibrils and LPS could be extended to study the effects of tau and α-synuclein aggregates on TLR4 activation.
Understanding how different protein aggregates influence Myddosome dynamics and downstream signaling pathways can provide insights into the mechanisms underlying neuroinflammation in neurodegenerative diseases. By elucidating the specific characteristics of Myddosome formation in response to various protein aggregates, researchers can uncover novel therapeutic targets and strategies for modulating TLR4 signaling in neurodegenerative disorders.