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.