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

The p75 neurotrophin receptor (p75NTR) 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 p75NTR ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75NTR ligand, LM11A-31, was administered orally to the Thy-1 hAPPLond/Swe (APPL/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 APPL/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 p75NTR is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.