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BACKGROUND: Tauopathies such as Alzheimer's disease (AD) are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau (MAPT) aggregating into neurofibrillary tangles (NFTs). O-linked ß-N-acetylglucosamine (O-GlcNAc) modifications have been suggested to regulate tau phosphorylation and aggregation and N-acetylglucosaminidase (OGA) removes GlcNAc moieties from proteins. METHODS: We investigated effects of the OGA inhibitor Thiamet G in rTg4510 primary neuronal cultures and in rTg4510 mice. The rTg4510 mice overexpress human tau harboring the P301L mutation and display an age-dependent progression of tau pathology including hyperphosphorylated tau species and NFTs. Aged rTg4510 mice exhibit a non-mnemonic behavioral defect involving a hyperactive phenotype that is associated with the progression of tau pathology. RESULTS: Thiamet G increased overall O-GlcNAc levels and crossed the blood brain barrier in rTg4510 mice. The free fraction of Thiamet G in the brain was 22-fold above the half maximal effective concentration (EC50) measured in rTg4510 primary neurons. Chronic Thiamet G treatment (18 weeks) initiated in young 6 week old rTg4510 mice increased brain O-GlcNAc levels and this corresponded with a significant reduction in soluble and insoluble hyperphosphorylated tau in aged 24 week old rTg4510 mice. Levels of normally phosphorylated P301L tau were not altered under these conditions. Reduction of hyperphosphorylated tau species by increased O-GlcNAcylation was associated with significant attenuation of hyperactivity in 24 week old rTg4510 mice. CONCLUSIONS: Our findings support the pharmacological inhibition of OGA as a potential therapeutic approach for the treatment of AD and other tauopathies.
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Enfermedad de Alzheimer , Tauopatías , Humanos , Animales , Ratones , Piranos , TiazolesRESUMEN
INTRODUCTION: The abnormal hyperphosphorylation of the microtubule-associated protein tau plays a crucial role in neurodegeneration in Alzheimer's disease (AD) and other tauopathies. METHODS: Highly specific and selective anti-pS396-tau antibodies have been generated using peptide immunization with screening against pathologic hyperphosphorylated tau from rTg4510 mouse and AD brains and selection in in vitro and in vivo tau seeding assays. RESULTS: The antibody C10.2 bound specifically to pS396-tau with an IC50 of 104 pM and detected preferentially hyperphosphorylated tau aggregates from AD brain with an IC50 of 1.2 nM. C10.2 significantly reduced tau seeding of P301L human tau in HEK293 cells, murine cortical neurons, and mice. AD brain extracts depleted with C10.2 were not able to seed tau in vitro and in vivo, demonstrating that C10.2 specifically recognized pathologic seeding-competent tau. DISCUSSION: Targeting pS396-tau with an antibody like C10.2 may provide therapeutic benefit in AD and other tauopathies.
RESUMEN
Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD.