title: Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers.
abstract: 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.
authors.affiliation: 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 90095-7334, USA. gbitan@mednet.ucla.edu
authors.forename: Aida
authors.initials: A
authors.lastname: Attar
authors.forename: Cristian
authors.initials: C
authors.lastname: Ripoli
authors.forename: Elisa
authors.initials: E
authors.lastname: Riccardi
authors.forename: Panchanan
authors.initials: P
authors.lastname: Maiti
authors.forename: Domenica D
authors.initials: DD
authors.lastname: Li Puma
authors.forename: Tingyu
authors.initials: T
authors.lastname: Liu
authors.forename: Jane
authors.initials: J
authors.lastname: Hayes
authors.forename: Mychica R
authors.initials: MR
authors.lastname: Jones
authors.forename: Kristin
authors.initials: K
authors.lastname: Lichti-Kaiser
authors.forename: Fusheng
authors.initials: F
authors.lastname: Yang
authors.forename: Greg D
authors.initials: GD
authors.lastname: Gale
authors.forename: Chi-Hong
authors.initials: CH
authors.lastname: Tseng
authors.forename: Miao
authors.initials: M
authors.lastname: Tan
authors.forename: Cui-Wei
authors.initials: CW
authors.lastname: Xie
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Straudinger
authors.forename: Frank-Gerrit
authors.initials: FG
authors.lastname: Klärner
authors.forename: Thomas
authors.initials: T
authors.lastname: Schrader
authors.forename: Sally A
authors.initials: SA
authors.lastname: Frautschy
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000627:therapeutic use; D001814:Blood-Testis Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005106:Exploratory Behavior / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008239:Lysine / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000977:Antiparasitic Agents; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; D016875:tau Proteins; D003577:Cytochrome P-450 Enzyme System; D008239:Lysine