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Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice
- Source :
- Acta Neuropathologica Communications, Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-23 (2020)
- Publication Year :
- 2020
- Publisher :
- BioMed Central, 2020.
-
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 small-molecule 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. Electronic supplementary material The online version of this article (10.1186/s40478-020-01034-0) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Male
Dendritic spine
Morpholines
Mice, Transgenic
Receptors, Nerve Growth Factor
Hippocampus
lcsh:RC346-429
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
medicine
Animals
Humans
Isoleucine
lcsh:Neurology. Diseases of the nervous system
biology
Chemistry
Kinase
Cyclin-dependent kinase 5
Research
Neurodegeneration
Calpain
Cofilin
medicine.disease
Cell biology
030104 developmental biology
Tauopathies
biology.protein
Phosphorylation
Neurology (clinical)
Tauopathy
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20515960
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica Communications
- Accession number :
- edsair.doi.dedup.....4e32d1ffc8aee40b4cf4281acf2ed359