Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass

Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.

Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases

Endoplasmic reticulum(ER)and mitochondria are tubular organelles with a characteristic“network structure”that facilitates the formation of inter-organellar connections.As a result,mitochondria-associated ER membranes(MAMs),a subdomain of the ER that is tightly linked to and communicates with mitochondria,serve multiple physiological functions including lipid synthesis and exchange,calcium signaling,bioenergetics,and apoptosis.Importantly,emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer’s disease,amyotrophic lateral sclerosis,and Parkinson’s disease.This review will focus on the architecture and function of MAMs and its involvement in the neurodegenerative diseases.

Mitochondrial dynamic abnormalities in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases.Neuronal mitochondria dysfunction is one of the earliest features of ALS.Mitochondria are highly dynamic organelles that undergo continuous fission,fusion,trafficking and turnover,all of which contribute to the maintenance of mitochondrial function.Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS.Here,we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS,and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS.

Posttranslational modifications of α-tubulin in alzheimer disease

Background:In Alzheimer disease(AD),hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities.Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls,however,this reduction did not coincide with the presence of paired helical filaments.The latter suggests the presence of compensatory mechanism(s)that stabilize microtubule dynamics despite the loss of tau binding and stabilization.Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules.Methods:In this study,we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry.Results:Consistent with our previous study,we found decreased levels ofα-tubulin in AD brain.Levels of tubulin with various posttranslational modifications such as polyglutamylation,tyrosination,and detyrosination were also proportionally reduced in AD brain,but,interestingly,there was an increase in the proportion of the acetylatedα-tubulin in the remainingα-tubulin.Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body.The number of processes containing polyglutamylated tubulin was well preserved in AD neurons.While there was a cell autonomous detrimental effect of NFTs on tubulin,this is likely a gradual and slow process,and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons.Conclusions:Overall,we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response.