RESUMO
Loss of dendritic spines and decline of cognitive function are hallmarks of patients with Alzheimer's disease (AD). Previous studies have shown that AD pathophysiology involves increased expression of a central nervous system-enriched protein tyrosine phosphatase called STEP (STriatal-Enriched protein tyrosine Phosphatase). STEP opposes the development of synaptic strengthening by dephosphorylating substrates, including GluN2B, Pyk2, and ERK1/2. Genetic reduction of STEP as well as pharmacological inhibition of STEP improve cognitive function and hippocampal memory in the 3×Tg-AD mouse model. Here, we show that the improved cognitive function is accompanied by an increase in synaptic connectivity in cell cultures as well as in the triple transgenic AD mouse model, further highlighting the potential of STEP inhibitors as a therapeutic agent.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Hipocampo , Memória , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Objective: To characterise perceptions of the Philadelphia Beverage Tax among low-income parents. Design: We conducted semi-structured interviews and administered demographic questions via telephone. We based the interview guide and initial codebook on a conceptual model illustrating perceived fairness and effectiveness as essential for successfully adopting food policies. We performed thematic analysis using NVivo 12. Setting: We recruited from a primary care paediatrics clinic in Philadelphia, Pennsylvania from July to August 2020. Participants: Philadelphia parents/caregivers of 2- to 11-year-old children with Medicaid insurance. Results: Participants were predominantly African American (97 %), female (100 %), and had annual household incomes <$50 000 (80 %). Participants were 26- to 72-years old, with an average aged child of 5 years (range 7 months to 20 years). Themes emerged regarding tax perceptions, revenue use and behaviour change due to the tax. Using revenue for highly valued programmes and accountability of city government to use revenue as promised were critical elements in perceptions of tax fairness. Some parents avoided the tax through cross-border shopping and buying drink powders or concentrates, influencing perceptions of tax effectiveness. The tax signalled the health dangers of sweetened beverage consumption to most parents. Conclusion: Our findings bring to light four key takeaways for policymakers designing sweetened beverage taxes. (1) Dedication of tax revenue to programmes highly valued by parents and (2) transparency in revenue spending may improve acceptability. (3) State or national taxes may be more effective at decreasing consumption due to cross-border shopping. (4) Pairing taxes with health promotion campaigns may enhance behaviour change.
Assuntos
Bebidas Adoçadas com Açúcar , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Pessoa de Meia-Idade , Pais , Philadelphia , Pobreza , Impostos , Estados UnidosRESUMO
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, with additional symptoms including attention deficit and hyperactivity, anxiety, impulsivity, and repetitive movements or actions. The majority of FXS cases are attributed to a CGG expansion that leads to transcriptional silencing and diminished expression of fragile X mental retardation protein (FMRP). FMRP, an RNA binding protein, regulates the synthesis of dendritically-translated mRNAs by stalling ribosomal translation. Loss of FMRP leads to increased translation of some of these mRNAs, including the CNS-specific tyrosine phosphatase STEP (STriatal-Enriched protein tyrosine Phosphatase). Genetic reduction of STEP in Fmr1 KO mice have diminished audiogenic seizures and a reversal of social and non-social anxiety-related abnormalities. This study investigates whether a newly discovered STEP inhibitor (TC-2153) could attenuate the behavioral and synaptic abnormalities in Fmr1 KO mice. TC-2153 reversed audiogenic seizure incidences, reduced hyperactivity, normalized anxiety states, and increased sociability in Fmr1 KO mice. Moreover, TC-2153 reduced dendritic spine density and improved synaptic aberrations in Fmr1 KO neuronal cultures as well as in vivo. TC-2153 also reversed the mGluR-mediated exaggerated LTD in brain slices derived from Fmr1 KO mice. These studies suggest that STEP inhibition may have therapeutic benefit in FXS.