title: Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model.
abstract: The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.
authors.affiliation: Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94304, USA.
authors.forename: Juliet K
authors.initials: JK
authors.lastname: Knowles
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Simmons
authors.forename: Thuy-Vi V
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Lilith
authors.initials: L
authors.lastname: Vander Griend
authors.forename: Youmei
authors.initials: Y
authors.lastname: Xie
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Julia
authors.initials: J
authors.lastname: Pollak
authors.forename: Timothy
authors.initials: T
authors.lastname: Chang
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Marion S
authors.initials: MS
authors.lastname: Buckwalter
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003072:Cognition Disorders / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D007532:Isoleucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009410:Nerve Degeneration / Q000517:prevention & control*; D016501:Neurites / Q000473:pathology*; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; C575077:LM11A-31; D008024:Ligands; D009025:Morpholines; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D007532:Isoleucine
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