A Small Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington's Disease

Abstract

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. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLC␥, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.

A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses

“…Increasing evidence reveals that reactive gliosis occurs in vulnerable regions of HD brains and strongly associated with HD pathogenesis39. In this study, we evaluated the effects of W20 on astrocytosis and microgliosis in BACHD mouse brains by immunostaining for GFAP and Iba-1.…”

Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease

“…However, data regarding TrkB / p75 NTR levels and their downstream signaling are not consistent among different animal models (Gharami et al, 2008; Xie et al, 2010; Simmons et al, 2013; Plotkin et al, 2014). In aged zQ175 KI HD mice, we observed significant decreased TrkB phosphorylation in the cell bodies of medium spiny neurons using validated antibodies.…”

TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination

“…Towards this end, several small molecule TrkB agonists have recently been developed, including 7, and adenosine A2A receptor agonists (Wehrman et al, 2007). LM22A-4 and 7,8-DHF have been shown to prevent neural cell death in a TrkB dependent manner in vitro, and also exert neuroprotective effects and promote functional recovery in a number of animal models of neurodegenerative disease (Simmons et al, 2013;Jiang et al, 2013;Zhang et al, 2014;Chang et al, 2002;Trapp and Nave, 2008;Massa et al, 2010;Jang et al, 2010). Interestingly, several recent studies have implicated BDNF in reducing the extent of demyelination and promoting remyelination using different animal models of CNS demyelination (VonDran et al, 2011;Linker et al, 2010), suggesting that activating BDNF signalling with small molecule BDNF mimetics is a potential therapeutic strategy to enhance CNS remyelination following a demyelinating insult.…”