During normal aging,there is a decline in all physiological functions in the organism.One of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive impairment.Agin...During normal aging,there is a decline in all physiological functions in the organism.One of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive impairment.Aging is one of the main risk factors for the development of neurodegenerative diseases,such as Alzheimer’s disease.One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates.The most studied brain aggregates are the senile plaques,formed by Aβpeptide;however,the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity.It is reported that neurons undergo severe mitochondrial dysfunction with age,with a decrease in adenosine 5′-triphosphate production,loss of the mitochondrial membrane potential,redox imbalance,impaired mitophagy,and loss of calcium buffer capacity.Interestingly,abnormal tau protein interacts with several mitochondrial proteins,suggesting that it could induce mitochondrial dysfunction.Nevertheless,whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown.A recent study of our laboratory shows that phosphorylated tau at Ser396/404(known as PHF-1),an epitope commonly related to pathology,accumulates inside mitochondria during normal aging.This accumulation occurs preferentially in synaptic mitochondria,which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals.Here,we review the main tau modifications promoting mitochondrial dysfunction,and the possible mechanism involved.Also,we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging.Finally,we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer’s disease,which could be considered as an early event in the neurodegenerative process.Thus,phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.展开更多
目的探索海洛因成瘾大鼠海马区蛋白激酶A(cAMP-dependent protein kinase,PKA)、tau蛋白磷酸化以及成对螺旋纤维(PHF)的改变。方法SD大鼠皮下渐增注射海洛因(1mg.kg-1.d-1逐日递增1mg.kg-1.d-1至20.kg-1.d-1维持10d)建立海洛因成瘾大鼠...目的探索海洛因成瘾大鼠海马区蛋白激酶A(cAMP-dependent protein kinase,PKA)、tau蛋白磷酸化以及成对螺旋纤维(PHF)的改变。方法SD大鼠皮下渐增注射海洛因(1mg.kg-1.d-1逐日递增1mg.kg-1.d-1至20.kg-1.d-1维持10d)建立海洛因成瘾大鼠动物模型。在海洛因成瘾大鼠海马区用免疫组织化学方法针对抗体PKA-α(cAMP-dependent protein kinase-α)、PKA-β(cAMP-dependent protein kinase-β)、tau(S396)、PHF-1(paried helical filaments-1)进行显色。结果海洛因成瘾组大鼠脑内PKA-α、PKA-β、tau(S396)、PHF-1(paried helical filaments-1)免疫染色均明显高于对照组。结论海洛因成瘾大白鼠脑内海马部位存在PKA含量升高、tau蛋白396位点异常磷酸化以及PHF形成。展开更多
基金supported by FONDECYT,No.11170546,CONICYT PAI,No.77170091(to CTR)FONDECYT,No.3210591(to CJ).
文摘During normal aging,there is a decline in all physiological functions in the organism.One of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive impairment.Aging is one of the main risk factors for the development of neurodegenerative diseases,such as Alzheimer’s disease.One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates.The most studied brain aggregates are the senile plaques,formed by Aβpeptide;however,the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity.It is reported that neurons undergo severe mitochondrial dysfunction with age,with a decrease in adenosine 5′-triphosphate production,loss of the mitochondrial membrane potential,redox imbalance,impaired mitophagy,and loss of calcium buffer capacity.Interestingly,abnormal tau protein interacts with several mitochondrial proteins,suggesting that it could induce mitochondrial dysfunction.Nevertheless,whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown.A recent study of our laboratory shows that phosphorylated tau at Ser396/404(known as PHF-1),an epitope commonly related to pathology,accumulates inside mitochondria during normal aging.This accumulation occurs preferentially in synaptic mitochondria,which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals.Here,we review the main tau modifications promoting mitochondrial dysfunction,and the possible mechanism involved.Also,we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging.Finally,we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer’s disease,which could be considered as an early event in the neurodegenerative process.Thus,phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.
文摘目的探索海洛因成瘾大鼠海马区蛋白激酶A(cAMP-dependent protein kinase,PKA)、tau蛋白磷酸化以及成对螺旋纤维(PHF)的改变。方法SD大鼠皮下渐增注射海洛因(1mg.kg-1.d-1逐日递增1mg.kg-1.d-1至20.kg-1.d-1维持10d)建立海洛因成瘾大鼠动物模型。在海洛因成瘾大鼠海马区用免疫组织化学方法针对抗体PKA-α(cAMP-dependent protein kinase-α)、PKA-β(cAMP-dependent protein kinase-β)、tau(S396)、PHF-1(paried helical filaments-1)进行显色。结果海洛因成瘾组大鼠脑内PKA-α、PKA-β、tau(S396)、PHF-1(paried helical filaments-1)免疫染色均明显高于对照组。结论海洛因成瘾大白鼠脑内海马部位存在PKA含量升高、tau蛋白396位点异常磷酸化以及PHF形成。
