A Small Molecule p75NTR Ligand, LM11A-31, Reverses Cholinergic Neurite Dystrophy in Alzheimer's Disease Mouse Models with Mid- to Late-Stage Disease Progression

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.

The recent development in synthesis and pharmacological evaluation of small molecule to treat Alzheimer's diseases: A review

“…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 (Simmons et al, 2014). Much effort has been devoted to developing effective therapeutic agents.…”

p75NTR and DR6 regulate distinct phases of axon degeneration demarcated by spheroid rupture

“…We next sought to determine whether p75NTR requires ligand to induce spheroid formation. Application of LM11A-31, a small nonpeptide molecule competitor of p75NTR ligand binding (Massa et al, 2006;Simmons et al, 2014), suppressed spheroid formation on wild-type sympathetic axons after NGF deprivation ( Supplementary Fig.5a-b). However, blocking brainderived neurotrophic factor (BDNF), which has been shown to activate p75NTR apoptotic signaling (Kohn et al, 1999), failed to inhibit development of spheroids on NGF deprived axons ( Supplementary Fig.5a-b).…”

The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides

“…A wealth of effort has been made through the years in combining simulation protocols with experimental research for enhancing a rational peptidomimetic design. Small molecules that mimic the NTs functionally or structurally have been designed and synthesized, expecting to be devoid of the aforementioned drawbacks [15][16][17][18][19].…”