Targeting tau in Alzheimer's disease:from mechanisms to clinical therapy

Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.

Tyrosine Hydroxylase as a Target for Deltamethrin in the Nigrostriatal Dopaminergic Pathway

Objective To study the effects of deltamethrin on tyrosine hydroxylase in nigrostriatum of male rats. Methods Sprague-Dawley rats were daily treated with deltamethrin at 6.25 or 12.5 mg/kg body weight by gavage for 10 days. Then HPLC-fluorescence detection was used to analyze the contents of dopamine （DA）, 3,4-dihydmxyphenylacetic acid （DOPAC） and homoranillic acid （HVA） in substantial nigra and striatum. The activities of tyrosine hydroxylase （TH） were also detected by HPLC-fluorescence detection. TH mRNA or TH protein levels were measured by RT-PCR and immunohistochemistry method. Results The content of DA in stfiatum was significantly decreased by the treatments, suggesting an inhibition of DA synthesis by deltamethrin. The contents of DA metabolites DOPAC and HVA increased, indicating increased dopamine turnover. Furthermore, deltamethrin significantly decreased the activity, as well as the mRNA and protein levels of TH. Conclusions These findings reveal a novel aspect of deltamethfin neurotoxicity and suggest tyrosine hydroxylase as a molecular target of deltamethin on dopamine metabolism in the nigrostriatal pathway.

STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17

In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.

Recombinant human erythropoietin ameliorates cognitive dysfunction of APP/PS1 mice by attenuating neuron apoptosis via HSP90β

Dear Editor,Recently,lower hemoglobin/anemia in the elderly is found to be associated with cognitive impairment and Alzheimer’s disease(AD),1 implying that erythropoietin(EPO)may be of benefit for AD.As a clinically safe-to-use drug,besides its hematopoietic function,recombinant human EPO(rhEPO)is reported to present multifaceted neuroprotective effects.2 Unfortunately,few clinical studies investigated the effect of rhEPO in AD patients.

STAT3 ameliorates cognitive deficits by positively regulatingthe expression of NMDARs in a mouse model of FTDP-17

In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3^(flox/flox) mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.