2,3,4-Trihydroxybenzophenone Disassembles Amyloid β Aggregates and Ameliorates Synaptic Deficits.

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Alzheimer's disease (AD) lacks disease-modifying therapies.
• Current amyloid-beta (Aβ)-targeting antibodies have limitations.
• Small molecules reducing toxic Aβ aggregates are needed.

Purpose of the Study:

• Investigate 2,3,4-trihydroxybenzophenone (THB) effects on Aβ₁-42 aggregation and disassembly.
• Assess THB's neuroprotective and synaptic function effects in vitro and in vivo.

Main Methods:

• In vitro assays for Aβ₁-42 aggregation and fibril disassembly.
• Cell viability and hippocampal slice electrophysiology.
• In vivo studies in Aβ₁-42 injected and 5XFAD mice (behavioral, histological, electrophysiological analyses).

Main Results:

• THB inhibited Aβ₁-42 aggregation and disassembled preformed fibrils.
• THB reduced Aβ₁-42-induced cell death and restored synaptic plasticity.
• THB decreased amyloid pathology, neuroinflammation, and improved memory in mouse models.

Conclusions:

• THB modulates pathogenic Aβ₁-42 assemblies.
• THB shows potential for Alzheimer's disease prevention or modification.
• Provides a basis for developing small-molecule Aβ modulators.