Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Nonfibrillar, low-molecular weight amyloid beta (Aβ) assemblies are implicated in Alzheimer's disease (AD) pathogenesis.
• Aβ dimers isolated from human brain extracts inhibit long-term potentiation (LTP) and impair memory consolidation.
• SDS-stable Aβ dimers may represent the fundamental units of synaptotoxic assemblies in AD.

Purpose of the Study:

• To understand the structure and properties of Aβ dimers.
• To investigate the role of Aβ dimers in the formation of toxic protein aggregates.
• To elucidate the mechanism by which Aβ assemblies mediate neurotoxicity.

Main Methods:

• Generation of synthetic disulfide-cross-linked Aβ(1-40) dimers (AβS26C)2 to mimic natural species.
• Analytical ultracentrifugation to determine dimer molecular weight and assess secondary structure.
• In vitro aggregation assays and thioflavin T binding to characterize aggregate formation.
• Electrophysiological recordings (LTP) in mouse hippocampal slices to assess neurotoxicity.

Main Results:

• Synthetic (AβS26C)2 dimers lacked detectable secondary structure and behaved as ~8.6 kDa species.
• Unlike wild-type Aβ, (AβS26C)2 did not affect hippocampal LTP directly.
• (AβS26C)2 rapidly formed stable, β-sheet-rich, protofibril-like assemblies that potently inhibited LTP, distinct from wild-type amyloid fibrils.

Conclusions:

• Aβ dimers can stabilize fibril intermediates through a mechanism separate from monomer aggregation.
• Higher molecular weight, prefibrillar Aβ assemblies, potentially originating from dimers, are the primary mediators of Aβ-induced neurotoxicity.
• These findings highlight the critical role of Aβ dimer structure and aggregation in Alzheimer's disease pathology.