Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model

Neurobiol Aging. 2013 Aug;34(8):2052-63. doi: 10.1016/j.neurobiolaging.2013.02.015. Epub 2013 Mar 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Cognition Disorders / prevention & control
  • Disease Models, Animal
  • Female
  • Isoleucine / administration & dosage
  • Isoleucine / analogs & derivatives*
  • Isoleucine / pharmacology
  • Isoleucine / therapeutic use
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Molecular Targeted Therapy
  • Morpholines / administration & dosage
  • Morpholines / pharmacology
  • Morpholines / therapeutic use*
  • Nerve Degeneration / prevention & control*
  • Neurites / pathology*
  • Receptors, Nerve Growth Factor / physiology*

Substances

  • Amyloid beta-Peptides
  • LM11A-31
  • Ligands
  • Morpholines
  • Receptors, Nerve Growth Factor
  • TNFRSF16 protein, mouse
  • Isoleucine