lm11a-31 and Alzheimer-Disease

Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cells, Cultured; Disease Models, Animal; Green Fluorescent Proteins; Hippocampus; Isoleucine; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morpholines; Neurites; Phosphorylation; Receptors, Nerve Growth Factor; rhoA GTP-Binding Protein; Signal Transduction; tau Proteins; Transfection

Microglial activation is a key pathological feature of Alzheimer's disease (AD). PET imaging of translocator protein 18 kDa (TSPO) is a strategy to detect microglial activation

Topics: Alzheimer Disease; Animals; Carbazoles; Cerebral Cortex; Disease Models, Animal; Hippocampus; Isoleucine; Mice; Microglia; Morpholines; Radiopharmaceuticals; Receptors, GABA; Sensitivity and Specificity

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cholinergic Neurons; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Female; Humans; Isoleucine; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morpholines; Nerve Degeneration; Neurites; Protective Agents; Receptor, Nerve Growth Factor; Signal Transduction

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-β-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.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition Disorders; Disease Models, Animal; Female; Isoleucine; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Targeted Therapy; Morpholines; Nerve Degeneration; Neurites; Receptors, Nerve Growth Factor