Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their
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RESEARCH
Small‑molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice Tao Yang1, Harry Liu1†, Kevin C. Tran1†, Albert Leng1, Stephen M. Massa2* and Frank M. Longo1*
Abstract In tauopathies, phosphorylation, acetylation, cleavage and other modifications of tau drive intracellular generation of diverse forms of toxic tau aggregates and associated seeding activity, which have been implicated in subsequent synaptic failure and neurodegeneration. Suppression of this wide range of pathogenic species, seeding and toxicity mechanisms, while preserving the physiological roles of tau, presents a key therapeutic goal. Identification and targeting of signaling networks that influence a broad spectrum of tau pathogenic mechanisms might prevent or reverse synaptic degeneration and modify disease outcomes. The p75 neurotrophin receptor ( p75NTR) modulates such networks, including activation of multiple tau kinases, calpain and rhoA-cofilin activity. The orally bioavailable smallmolecule p75NTR modulator, LM11A-31, was administered to tauP301S mice for 3 months starting at 6 months of age, when tau pathology was well established. LM11A-31 was found to reduce: excess activation of hippocampal cdk5 and JNK kinases and calpain; excess cofilin phosphorylation, tau phosphorylation, acetylation and cleavage; accumulation of multiple forms of insoluble tau aggregates and filaments; and, microglial activation. Hippocampal extracts from treated mice had substantially reduced tau seeding activity. LM11A-31 treatment also led to a reversal of pyramidal neuron dendritic spine loss, decreased loss of dendritic complexity and improvement in performance of hippocampal behaviors. These studies identify a therapeutically tractable upstream signaling module regulating a wide spectrum of basic mechanisms underlying tauopathies.
Introduction In tauopathies, pathological tau phosphorylation and other post-translational modifications (PTMs), along with tau misfolding, lead to formation of toxic *Correspondence: [email protected]; [email protected] † Harry Liu and Kevin C. Tran equal contributions to this work 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Room H3160, Stanford, CA 94305, USA 2 Department of Neurology, San Francisco Veterans Affairs Health Care System and University of California, San Francisco, 4150 Clement St., San Francisco, CA 94121, USA
intermediates involving a sequence of tau monomers, oligomers, protofibrils and filamentous species, resulting in the accumulation of neurofibrillary tangles (NFTs). NFTs are considered to be inert, while pre-NFT intermediates promote tau seeding [33], loss of dendritic spines and synapses [24, 29, 31] and microglial activation [42, 54]. Filamentous forms of tau identified by PET tracers demonstrate a notable longitudinal association with grey matter degeneration [40]. Numerous challenges in tauopathy therapeutics have b
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