Abstract
A significant hallmark of Alzheimer’s disease is the formation of senile plaques in the brain due to the unbalanced levels of amyloid-beta (Aβ). However, although how Aβ is produced from amyloid precursor proteins is well understood, little is known regarding the clearance and metabolism of various Aβ aggregates from the brain. Similarly, little is known regarding how astrocytes internalize and degrade Aβ, although astrocytes are known to play an important role in plaque maintenance and Aβ clearance. The objective of this study is to investigate the cellular mechanisms that mediate the internalization of soluble monomeric versus oligomeric Aβ by astrocytes. We used a combination of laser confocal microscopy and genetic and pharmacological experiments to dissect the internalization of sAβ42 and oAβ42 and their postendocytic transport by U87 human brain astrocytoma cell line. Both Aβ42 species were internalized by U87 cells through fluid phase macropinocytosis, which required dynamin 2. Depleting LDL receptor-related protein 1 (LRP1) decreased sAβ42 uptake more significantly than that of oAβ42. We finally show that both Aβ42 species were rapidly transported to lysosomes through an endolytic pathway and subjected to proteolysis after internalization, which had no significant toxic effects to the U87 cells under relatively low concentrations. We propose that macropinocytic sAβ42 and oAβ42 uptake and their subsequent proteolytic degradation in astroglial cells is a significant mechanism underlying Aβ clearance from the extracellular milieu. Understanding the molecular events involved in astrocytic Aβ internalization may identify potential therapeutic targets for Alzheimer’s disease.
Highlights
Senile plaques in the brain are one of the hallmarks of Alzheimer’s disease (AD)
It has been reported that only 5% of AD cases is due to Ab overproduction arising from mutations in the amyloid precursor protein (APP) gene or in APP processing enzymes, whereas the majority (95%) of so-called sporadic AD cases are likely caused by dysfunctions in Ab solubility, endocytosis, degradation, transcytosis, and removal [2]
Thioflavin T (ThT) fluorescence increased in a nearly linear-manner after titration with oligomeric Ab42 solution with concentrations ranging from 0 to 30 mM, which confirmed that these oligomers bound to ThT
Summary
Senile plaques in the brain are one of the hallmarks of Alzheimer’s disease (AD). The main component of these senile plaques is amyloid-beta (Ab), a metabolic product of amyloid precursor protein (APP). Steady-state levels of Ab in the normal brain are maintained by a balance between its production and clearance. This balance is broken in the AD brain due to either Ab overproduction or reduced Ab clearance. Ab can accumulate in the brain and form amyloid plaques that cause dementia and neurodegeneration [1]. Despite the dramatic progress that has been achieved in understanding how Ab is produced from APP, the mechanisms of Ab aggregation, clearance from the brain, and metabolism remain unclear [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
