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Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers


Year of Publication:
Contact PI Name:
Gal Bitan
Contact PI Affiliation:
Department of Neurology, University of California at Los Angeles, Los Angeles, California, USA
Aida Attar, Cristian Ripoli, Elisa Riccardi, Panchanan Maiti, Domenica D. Li Puma, Tingyu Liu, Jane Hayes, Mychica R. Jones, Kristin Lichti-Kaiser, Fusheng Yang, et al.,
Primary Reference (PubMED ID):
Funding Source:
University of California-Los Angeles Jim Easton Consortium for Alzheimer’s Drug Discovery
American Health Assistance Foundation
National Institute on Aging (NIA)
Robert James Graves Foundation
Study Goal and Principal Findings:

The "molecular tweezer" CLR01 is a broad-spectrum inhibitor of abnormal protein self-assembly, which acts by binding selectively to Lys residues. CLR01 has been tested in several in vitro and in vivo models of amyloidosis, and 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 the inventors 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, it was shown that CLR01 effectively inhibited synaptotoxicity induced by the amyloid beta 42 peptide, including >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, it was revealed that CLR01 crossed the mouse blood–brain barrier at ~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 peptide 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 (APP). 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.

Bibliographic Notes:
Full Author List: Aida Attar, Cristian Ripoli, Elisa Riccardi, Panchanan Maiti, Domenica D. Li Puma, Tingyu Liu, Jane Hayes, Mychica R. Jones, Kristin Lichti-Kaiser, Fusheng Yang, Greg D. Gale, Chi-hong Tseng, Miao Tan, Cui-Wei Xie, Jeffrey L. Straudinger, Frank-Gerrit Klärner, Thomas Schrader, Sally A. Frautschy, Claudio Grassi, Gal Bitan.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Amyloidogenic Proteins

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Load
Activated Microglia
Dendritic Spines
Cell Biology
Neuroprotection-Amyloid Neurotoxicity
Long Term Potentiation (LTP)
Input/Output (I/O) Curve
Blood Brain Barrier Penetration
Drug Concentration-Plasma
General Behavior
Body Weight
CYP450 Inhibition
Microsomal Stability