# Binding of ApoE Isoforms to Aβ Peptides and Effects on Their Fibrillization

## TL;DR

This study explores how different forms of ApoE protein bind to Aβ peptides and influence their formation into harmful fibrils linked to Alzheimer's disease.

## Contribution

The study provides new insights into the binding affinities and fibrillization effects of ApoE isoforms on Aβ peptides.

## Key findings

- ApoE3 binds Aβ1–42 with the strongest affinity (Kd = 0.72 μM), while ApoE4 binds it the weakest (Kd = 2.80 μM).
- ApoE4 shows the strongest binding to Aβ1–40 (Kd = 1.59 μM), and ApoE2 the weakest (Kd = 5.29 μM).
- ApoE inhibits Aβ1–42 fibrillization at substoichiometric concentrations, with ApoE4 having the strongest inhibitory effect.

## Abstract

Alzheimer’s
disease (AD) is the most widespread neurodegenerative
disease, strongly linked to amyloid depositions in the brain consisting
of amyloid β (Aβ) peptides. The likelihood of developing
late-onset Alzheimer’s disease (LOAD) is influenced by the
specific isoforms of apolipoprotein E (ApoE), with ApoE4 being the
strongest known genetic risk factor for LOAD. Strong evidence suggests
that ApoE impacts AD by modulating Aβ aggregation and clearance,
although the precise molecular mechanisms remain incompletely understood.
Microscale thermophoresis (MST) is a powerful technique for characterizing
molecular interactions in solution, which has been used to determine
various binding constants, although not the binding of ApoE to Aβ
peptides. MST results show that ApoE isoforms bind Aβ1–40
and Aβ1–42 with low micromolar affinity. For Aβ1–42,
ApoE3 shows the strongest binding (K
d =
0.72 μM) and ApoE4 shows the weakest binding (K
d = 2.80 μM). For Aβ1–40, ApoE4 shows
the strongest binding (K
d = 1.59 μM)
and ApoE2 shows the weakest binding (K
d = 5.29 μM). The MST results show that ApoE interacts with
Aβ peptides at supraphysiological peptide concentrations. However,
ApoE inhibited the fibrillization of Aβ1–42 peptide at
substoichiometric concentrations, which might be related to blocking
Aβ fibril elongation in vivo. The estimated IC50 values
indicate that ApoE4 has a slightly stronger, and ApoE2 a slightly
weaker, inhibitory effect on Aβ1–42 fibrillization.