A small molecule p75 ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model |
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Authors: | Juliet K. Knowles Danielle A. Simmons Thuy-Vi V. Nguyen Lilith Vander Griend Youmei Xie Hong Zhang Tao Yang Julia Pollak Timothy Chang Ottavio Arancio Marion S. Buckwalter Tony Wyss-Coray Stephen M. Massa Frank M. Longo |
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Affiliation: | 1. Department of Neurology and Neurological Science, Stanford University, Stanford, CA, USA;2. Department of Neurology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA;3. Department of Pathology and Taub Institute, Columbia University, New York, NY, USA;4. Palo Alto Veterans Affairs Health Care System, Palo Alto, CA, USA;5. Department of Neurology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA;6. Laboratory for Computational Neurochemistry and Drug Discovery, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA;g Department of Neurology, University of California–San Francisco, San Francisco, CA, USA |
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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. |
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Keywords: | Alzheimers' disease p75 neurotrophin receptor Neuritic dystrophy LM11A-31 |
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