TARGETING SOLUBLE AMYLOID-BETA OLIGOMERS WITH A NOVEL NANOBODY

Area of Science:

• Neuroscience
• Biochemistry
• Immunology

Background:

• The amyloid cascade hypothesis suggests amyloid plaques and Tau tangles cause neuronal death in Alzheimer's disease (AD).
• Emerging evidence highlights soluble amyloid-β oligomers (SAβOs) as early contributors to AD pathology, preceding plaque formation.
• SAβOs independently impair memory and cognitive function, even without plaques.

Approach:

• Developed a novel anti-SAβO nanobody (E3) using an alpaca immunized with SAβO.
• Characterized the E3 nanobody through in-vitro assays and in-vivo studies in 5XFAD mice.
• Utilized fluorescein (FAM)-labeled E3 nanobody for recognition and imaging of amyloid species.

Key Points:

• The E3 nanobody recognizes both SAβOs and amyloid-β plaques in 5XFAD mice.
• E3 nanobody successfully crosses the blood-brain barrier to bind brain amyloid species.
• Distinct spatial distribution observed: SAβOs associate with neurons, while plaques are extracellular.

Conclusions:

• SAβOs and amyloid plaques exhibit different morphologies and brain distributions.
• The E3 nanobody demonstrates potential as a diagnostic tool for Alzheimer's disease.
• The nanobody holds promise for theranostic applications in AD management.