A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression.

Danielle A Simmons,Stephen M Massa,Carly Finkle,Nadia P Belichenko,Gargi Banerjee,Frank M Longo,Juliet K Knowles,Elizabeth J Coulson

doi:10.1371/journal.pone.0102136

Abstract

Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6–8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12–13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.

Highlights

Degeneration of basal forebrain cholinergic neurons (BFCN) and their neurites is a major contributing factor to the cognitive dysfunction associated with Alzheimer’s disease (AD)
This study examined whether LM11A-31 could arrest or reverse the degeneration of cholinergic neurites in two well characterized AD models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576 mice, with treatment beginning in mid- to late stages of disease progression characterized by the presence of abundant amyloid deposits, well established BFCN degeneration, and memory deficits apparent in multiple testing paradigms [14,16,19,20,21]
Patients [24,25] and mouse models [26,27] with late-stage pathology and p75NTR is the target of LM11A-31, we determined whether p75NTR immunostaining was increased in the basal forebrain of APPL/S mice at the ages involved in this study, and if levels were affected by the ligand, which could suggest target engagement

Summary

Introduction

Degeneration of basal forebrain cholinergic neurons (BFCN) and their neurites is a major contributing factor to the cognitive dysfunction associated with Alzheimer’s disease (AD). BFCNs were found to degenerate when Ab oligomers were delivered to the brains of wild-type (WT) but not p75NTR deficient mice [7], and this degeneration was prevented by functionally removing the neurotrophin-binding domain of the receptor in an AD mouse model [8]. Together, these observations indicate that p75NTR signaling plays a necessary role in enabling Ab-induced degeneration and implicate it as an AD therapeutic target [9,10,11]

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Results

Conclusion