Small molecule modulation of the p75 neurotrophin receptor promotes dendritic spine resilience to pathogenic tau species and reduces their accumulation.

In tauopathies, such as Alzheimer’s disease (AD), oligomeric tau (oTau) can induce tau hyperphosphorylation and further oligomerization, contributing to dendrite and dendritic spine degeneration. The p75 neurotrophin receptor (p75NTR), which regulates signaling that overlaps with tauopathy-related degenerative pathways, is a promising therapeutic target. LM11A-31, a small-molecule p75NTR modulator, downregulates p75NTR’s degenerative signaling and upregulates signaling that promotes dendritic and synaptic integrity. In a tauopathy mouse model, LM11A-31 reversed spine loss in hippocampal pyramidal neurons and improved performance on behavioral tests of hippocampal function. In a Phase 2a randomized, placebo-controlled AD clinical trial, LM11A-31 slowed the progression of synaptic degeneration biomarkers. In the present study, we tested the hypothesis that LM11A-31 enhances resilience of spines and dendrites to pathological forms of tau and/or inhibits the formation and accumulation of pathological tau species. We found that LM11A-31 prevented degeneration of spines and dendrites in cultured hippocampal neurons exposed to recombinant oTau or oTau-containing hippocampal extract fractions from PS19 tauopathy mice. Treating PS19 mice with LM11A-31 reduced the degeneration-promoting activity in oTau-containing hippocampal extract fractions. In cultured hippocampal neurons, LM11A-31 inhibited excess tau phosphorylation and aggregation induced by oTau and counteracted oTau-induced abnormalities in RhoA, PKC, LIMK1, and cofilin signaling, a signaling module known to regulate spine integrity. The ability of LM11A-31 to confer resilience to dendritic spines was partially dependent on LIMK1 activity. These findings demonstrate that small-molecule modulation of p75NTR by LM11A-31 both reduces the accumulation of pathological tau species and promotes resilience against oTau-induced dendritic spine degeneration, exemplifying a “dual-mechanism” therapeutic approach for tauopathies.