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

NEUROBIOLOGY OF AGING

卷:34

Article

Knowles, Juliet K.^1,2  Simmons, Danielle A.¹  Nguyen, Thuy-Vi V.¹  Vander Griend, Lilith¹  Xie, Youmei²  Zhang, Hong^3,4  Yang, Tao¹  Pollak, Julia¹  Chang, Timothy¹  Arancio, Ottavio^3,4  Buckwalter, Marion S.¹  Wyss-Coray, Tony^1,5  Massa, Stephen M.^6,7,8  Longo, Frank M.¹ 

[1] Stanford Univ, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA

[2] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA

[3] Columbia Univ, Dept Pathol, New York, NY USA

[4] Columbia Univ, Taub Inst, New York, NY USA

[5] Palo Alto Vet Affairs Hlth Care Syst, Palo Alto, CA USA

[6] San Francisco VA Med Ctr, Dept Neurol, San Francisco, CA USA

[7] San Francisco VA Med Ctr, Lab Computat Neurochem & Drug Discovery, San Francisco, CA USA

[8] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

关键词: Alzheimers' disease;    p75 neurotrophin receptor;    Neuritic dystrophy;    LM11A-31;   

DOI  :  10.1016/j.neurobiolaging.2013.02.015

来源: Elsevier

【 摘 要 】

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-beta-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. (c) 2013 Elsevier Inc. All rights reserved.

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