Pharmacological Co-Activation of TrkB and TrkC Receptor Signaling Ameliorates Striatal Neuropathology and Motor Deficits in Mouse Models of Huntington's Disease.

Background: Loss of neurotrophic support in the striatum, particularly reduced brain-derived neurotrophic factor (BDNF) levels, contributes importantly to Huntington's disease (HD) pathogenesis. Another neurotrophin (NT), NT-3, is reduced in the cortex of HD patients; however, its role in HD is unknown. BDNF and NT-3 bind with high affinity to the tropomyosin receptor-kinases (Trk) B and TrkC, respectively.

Alzheimer's associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia.

The goal of this study was to determine the chronic impact of stroke on the manifestation of Alzheimer's disease (AD) related pathology and behavioral impairments in mice. To accomplish this goal, we used two distinct models. First, we experimentally induced ischemic stroke in aged wildtype (wt) C57BL/6 mice to determine if stroke leads to the manifestation of AD-associated pathological β-amyloid (Aβ) and tau in aged versus young adult wt mice.

TSPO-PET imaging using [18F]PBR06 is a potential translatable biomarker for treatment response in Huntington's disease: preclinical evidence with the p75NTR ligand LM11A-31.

Huntington's disease (HD) is an inherited neurodegenerative disorder that has no cure. HD therapeutic development would benefit from a non-invasive translatable biomarker to track disease progression and treatment response. A potential biomarker is using positron emission tomography (PET) imaging with a translocator protein 18 kDa (TSPO) radiotracer to detect microglial activation, a key contributor to HD pathogenesis.

[F]GE-180 PET Detects Reduced Microglia Activation After LM11A-31 Therapy in a Mouse Model of Alzheimer's Disease.

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 . Here we assessed flutriciclamide ([F]GE-180), a new second-generation TSPO-PET radiotracer, for its ability to monitor response to LM11A-31, a novel AD therapeutic in clinical trials.

Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity.

Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation.

A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.

Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington’s disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target.

PET imaging of translocator protein (18 kDa) in a mouse model of Alzheimer's disease using N-(2,5-dimethoxybenzyl)-2-18F-fluoro-N-(2-phenoxyphenyl)acetamide.

Unlabelled: Herein we aimed to evaluate the utility of N-(2,5-dimethoxybenzyl)-2-(18)F-fluoro-N-(2-phenoxyphenyl)acetamide ((18)F-PBR06) for detecting alterations in translocator protein (TSPO) (18 kDa), a biomarker of microglial activation, in a mouse model of Alzheimer's disease (AD).

Methods: Wild-type (wt) and AD mice (i.e.

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

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.

Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AβPP(L/S) transgenic mice.

The p75 neurotrophin receptor (p75NTR) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach.

A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease.

Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD.

The "Down syndrome critical region" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome.

Down syndrome (DS) can be modeled in mice segmentally trisomic for mouse chromosome 16. Ts65Dn and Ts1Cje mouse models have been used to study DS neurobiological phenotypes including changes in cognitive ability, induction of long-term potentiation (LTP) in the fascia dentata (FD), the density and size of dendritic spines, and the structure of synapses. To explore the genetic basis for these phenotypes, we examined Ts1Rhr mice that are trisomic for a small subset of the genes triplicated in Ts65Dn and Ts1Cje mice.

Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: evidence for disruption of neuronal networks.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene MECP2. Girls with RTT show dramatic changes in brain function, but relatively few studies have explored the structure of neural circuits. Examining two mouse models of RTT (Mecp2B and Mecp2J), we previously documented changes in brain anatomy.

Evidence for both neuronal cell autonomous and nonautonomous effects of methyl-CpG-binding protein 2 in the cerebral cortex of female mice with Mecp2 mutation.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Few studies have explored dendritic morphology phenotypes in mouse models of RTT and none have determined whether these phenotypes in affected females are cell autonomous or nonautonomous. Using confocal microscopy analysis we have examined the structure of dendrites and spines in the motor cortex of wild-type (WT) and Mecp2-mutant mice expressing green fluorescent protein (GFP).

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome.

Rett syndrome (RTT) is caused by mutations in the X-linked gene MECP2. While patients with RTT show widespread changes in brain function, relatively few studies document changes in brain structure and none examine in detail whether mutations causing more severe clinical phenotypes are linked to more marked changes in brain structure. To study the influence of MeCP2-deficiency on the morphology of brain areas and axonal bundles, we carried out an extensive morphometric study of two Mecp2-mutant mouse models (Mecp2B and Mecp2J) of RTT.