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

Abstract

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.

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…To the extent that ERK signaling mediates any of the toxic actions of Aβ, this pathway may also contribute to AD. Data consistent with hypothesis come from studies using a synthetic p75 neurotrophin receptor ligand, LM11A-31, which was found to inhibit Aβ-induced synaptic dysfunction and memory loss [70].…”

Characterization of Periodic Acid-Schiff-Positive Granular Deposits in the Hippocampus of SJL/J Mice

“…5, 2015 PAS-POSITIVE HIPPOCAMPAL GRANULES IN SJL/J MICEthe presented findings warrant further investigations on this topic. In fact, p75 NTR is a pivotal molecule in many neurodegenerative diseases, such as Alzheimer's disease, and plays a crucial role in many demyelinating diseases (Knowles et al 2013;Lempp et al 2014 ).…”

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

“…Interestingly, cortical p75 NTR levels were similar between genotypes ( Figure 1, B and D). To analyze whether deregulation of p75 NTR levels also occurs in humans, we examined hippocampal and cortical tissue from controls and decline and neuritic dystrophy in AD mouse models (27)(28)(29). In this scenario, we were interested to explore whether p75 NTR plays a role in different memory deficits in HD.…”