Differentiating Alzheimer disease-associated aggregates with small molecules.

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer disease diagnosis relies on postmortem identification of beta-amyloid plaques and tau tangles.
• Alzheimer pathology often co-occurs with Lewy body disease, involving alpha-synuclein aggregates.
• Protein aggregates in these diseases share cross-beta-sheet structures, complicating molecular probe development.

Purpose of the Study:

• To assess the feasibility of creating small molecule probes that can selectively distinguish tau aggregates from beta-amyloid and alpha-synuclein.
• To identify molecules with high binding affinity and selectivity for specific protein aggregate types.

Main Methods:

• Screened a library of 72,455 small molecules.
• Utilized Thioflavin S fluorescence assays to identify antagonists of tau-aggregate-mediated changes.
• Performed secondary screens to determine relative binding affinities for tau, beta-amyloid, and alpha-synuclein aggregates.

Main Results:

• Achieved greater than 10-fold binding selectivity among the different protein aggregate substrates.
• Identified specific molecular features, including at least three aromatic or rigid moieties connected by two rotatable bonds, associated with tau aggregate selectivity.

Conclusions:

• Small molecule probes can be developed to selectively target and differentiate between tau, beta-amyloid, and alpha-synuclein aggregates.
• This selectivity is crucial for advancing diagnostic tools for complex neurodegenerative disorders like Alzheimer disease and Lewy body disease.