Journal
BRAIN
Volume 135, Issue -, Pages 3735-3748Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/aws289
Keywords
Alzheimer's disease; amyloid; inhibitor; synaptotoxicity; drug development
Categories
Funding
- University of California-Los Angeles Jim Easton Consortium for Alzheimer's Drug Discovery and Biomarker Development
- American Health Assistance Foundation [A2008-350]
- RJG Foundation [20095024]
- Cure Alzheimer's Fund grant
- Individual Pre-doctoral National Research Service [1F31AG037283]
- National Institute of Health [R01AG021975]
- Veteran's Administration
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Alzheimer's disease is a devastating cureless neurodegenerative disorder affecting > 35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid beta protein and the microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid beta protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer's disease-associated synaptotoxicity and reduce Alzheimer's disease-like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid beta protein, including similar to 80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood-brain barrier at similar to 2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid beta protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid beta protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer's disease and related disorders.
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