Elsevier

Neurobiology of Aging

Volume 34, Issue 8, August 2013, Pages 2052-2063
Neurobiology of Aging

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

https://doi.org/10.1016/j.neurobiolaging.2013.02.015Get rights and content
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Abstract

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.

Keywords

Alzheimers' disease
p75 neurotrophin receptor
Neuritic dystrophy
LM11A-31

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D.A.S. and T.-V.V.N. are co-second authors and contributed equally to this work.