Protection of primary neurons and mouse brain from Alzheimer's
pathology by molecular tweezers.
Attar A, Ripoli C, Riccardi E, Maiti P, Li Puma DD, Liu T, Hayes J, Jones MR, Lichti-Kaiser K, Yang F, Gale
GD, Tseng CH, Tan M, Xie CW, Straudinger JL, Klärner FG, Schrader T, Frautschy SA, Grassi C, Bitan G.
Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles,
Neuroscience Research Building 1, Room 451, 635 Charles E. Young Drive South, Los Angeles, CA 900957334, USA. gbitan@mednet.ucla.edu.
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 β
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 β 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 β
protein, 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, we found 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 β 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 β 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.