# Amyloid β—Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology

## TL;DR

This paper shows how amyloid beta-42 removes cholesterol from membranes, which speeds up its aggregation and worsens Alzheimer's disease.

## Contribution

The novel finding is that Aβ42 can extract cholesterol from membranes, linking this process to amyloid aggregation and AD progression.

## Key findings

- Aβ42 removes cholesterol from membranes at low, physiological concentrations.
- Extracted cholesterol accelerates Aβ42 aggregation on membranes.
- Cholesterol depletion weakens membranes and may cause synapse loss in Alzheimer's.

## Abstract

The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42‐residue form of the amyloid‐β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability. Extracted cholesterol interacts with Aβ42 and accelerates its on‐membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates Aβ42 aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes resulted in three major AD‐related events. First, free cholesterol catalyzes the assembly of Aβ42 in aggregates, which is the mechanism by which physiologically important Aβ42 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane‐bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD.

The interplay between the cholesterol metabolism and assembly of Aβ42 (Amyloid beta‐42) peptide in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane at physiologically relevant low concentrations. Extracted cholesterol interacts with Aβ42 and accelerates its on‐membrane aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes, in addition to the assembly of Aβ42 aggregates, results in the accumulation of cholesterol in the brain and a decrease in membrane stiffness, which are the major risk factors associated with AD development and progression.