Tau and axonopathy in neurodegenerative disorders

The microtubule (MT)-associated protein (MAP) tau in neurons has been implicated as a significant factor in the axonal growth, development of neuronal polarity, and the maintenance of MT dynamics. Tau is localized to the axon, and is known to promote MT assembly and to stabilize axonal MTs. These functions of tau are primarily regulated by the activities of protein kinases and phosphatases. In Alzheimer's disease and other neurodegenerative disorders, abundant filamentous tau inclusions are found to be major neuropathological characteristics of these diseases. Both somato-dendritic and axonal tau lesions appear to be closely associated with axonal disruption. Furthermore, recent discoveries of pathogenic mutations on the tau gene suggest that abnormalities of tau alone are causative of neurodegeneration. Finally, analyses of transgenic mice that express human tau proteins have enabled in vivo quantitative assessments of axonal functions and have provided information about mechanistic relationships between pathological alteration of tau and axonal degeneration.     

Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders

Neurofibrillary tangles occur in a number of apparently distinct neurodegenerative diseases and in normal aging of the human brain. Antibodies raised against Alzheimer's disease paired helical filaments immunolabel the tangles seen in all other tangle-associated disorders examined to date. The neuronal microtubule-associated protein, tau, has recently been identified as an antigenic component of neurofibrillary tangles and senile plaque neurites in Alzheimer's disease. Three different polyclonal antibodies with strong tau immunoreactivity are examined in this study. These antibodies were found to immunostain tangles in normal aged brain and in brains affected by a range of neurodegenerative disorders, including Down's syndrome, Alzheimer's disease plus Parkinson's disease, progressive supranuclear palsy, and the parkinsonism-dementia complex of Guam, as well as Pick bodies in Pick's disease. The findings further illustrate the relative nonspecificity of neurofibrillary lesions in neurodegenerative disorders.     

Sweat gland pathology in neurodegenerative disorders]

Ultrastructural pathology on sweat gland epithelium was studied in various neurodegenerative disorders; neuronal ceroid-lipofuscinosis (NCL), Lafora disease, mucopolysaccharidosis, GM1 gangliosidosis, Nieman-Pick disease, Fabry disease, Krabbe disease and metachromatic leukodystrophy (MLD). Every disease had its own characteristic inclusions in sweat gland epithelium. Curvilinear profiles and fingerprint patterns were seen in NCL, but there were no morphological differences among late infantile, early juvenile and juvenile types. On the other hand, the granular matrix was characteristic of the infantile type. The presence of specific inclusions in a 23-year-old female carrier with Fabry disease indicated that a skin biopsy was one of the useful methods to detect a female carrier. In MLD and Krabbe disease, there were disease specific inclusions in sweat gland epithelium. These results indicate that the sweat glands should be investigated when a skin biopsy is performed for the diagnosis of neurodegenerative diseases.     

Tau protein isoforms, phosphorylation and role in neurodegenerative disorders

Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intraneuronal and glial fibrillar lesions described in Alzheimer’s disease and numerous neurodegenerative disorders referred to as ‘tauopathies’. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.     

Tau in neurodegenerative diseases: Tau phosphorylation and assembly

The possible link between tau phosphorylation and tau assembly in these neurodegenerative diseases known as tauopathies is described. Additionally, this link is supported by an in vitro experiment showing the higher capacity of phosphotau to assemble in some specific conditions; and, by a recently reported experiment using a tau transgenic mouse model.     

Review: Axon pathology in age‐related neurodegenerative disorders

‘Dying back’ axon degeneration is a prominent feature of many age‐related neurodegenerative disorders and is widespread in normal ageing. Although the mechanisms of disease‐ and age‐related losses may differ, both contribute to symptoms. Here, we review recent advances in understanding axon pathology in age‐related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. In particular, we highlight the importance of axonal transport, autophagy, traumatic brain injury and mitochondrial quality control. We then place these disease mechanisms in the context of changes to axons and dendrites that occur during normal ageing. We discuss what makes ageing such an important risk factor for many neurodegenerative disorders and conclude that the processes of normal ageing and disease combine at the molecular, cellular or systems levels in a range of disorders to produce symptoms. Pathology identical to disease also occurs at the cellular level in most elderly individuals. Thus, normal ageing and age‐related disease are inextricably linked and the term ‘healthy ageing’ downplays the important contributions of cellular pathology. For a full understanding of normal ageing or age‐related disease we must study both processes.     

Apoptosis: a key in neurodegenerative disorders

Apoptosis is an important process in the development of the nervous system. Typically, approximately 50% of the neurons apoptose during neurogenesis before the nervous system matures. However, recent paradigms implicate premature apoptosis and/or aberrations in the fine control of neuronal apoptosis in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, stroke, brain trauma, spinal cord injury, and diabetic neuropathy. This review will focus on the current concepts salient to understanding the apoptosis death program, the mediators and control of cellular apoptosis, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. The discussion will also highlight current advances in methodology, such as utilization of neuronal cell lines and mutant animal models, in investigations of neuronal apoptotic death. The knowledge of apoptosis mechanisms could underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.     

New aspects of the pathology of neurodegenerative disorders as revealed by ubiquitin antibodies

Summary Ubiquitin has previously been identified as a component of neuronal inclusions in neurodegenerative disorders. In this investigation, we examined tissue from cases of Alzheimer's disease (AD), Pick's discase, Parkinson's disease (PD), and progressive supranuclear palsy (PSP) to identify previously unrecognized ubiquitinated structures and to assess the evolution of neuronal inclusions. In AD, approximately 60% of neurofibrillary tangles (NFTs) that were stained with an anti-paired helical filaments (PHF) serum were identified by the ubiquitin antibodies. Extracellular NFTs were not labelled with anti-PHF but were unlabelled or weakly labelled with anti-ubiquitin antibodies. In Pick's disease, most Pick bodies were strongly labelled by the ubiquitin antibodies, and in addition some hippocampal CA1 neurones contained granular or strand-like ubiquitin-immunoreactive (IR) inclusions associated with more typical Pick bodies. Typical Lewy bodies in PD cases showed an unlabelled central core with an outer ring intensely labelled by ubiquitin antibodies. Pale bodies in pigmented substantia nigra neurones appeared as large well-defined, rounded structures without an identifiable core or peripheral zone. Some pale bodies were unlabelled by ubiquitin antibodies, but others showed labelling of variable intensity. Pale bodies which were labelled by ubiquitin antibodies tended also to be labelled by BF10, a monoclonal antibody against phosphorylated neurofilaments. We suggest that pale bodies in PD may represent stages in the formation of Lewy bodies. In addition, we observed numerous spindle-shaped ubiquitin-IR swellings of dendrites of pigmented substantia nigra neurones. In contrast to inclusions of AD and Pick's disease, the PHF-positive fibrillary neuronal inclusions of PSP were either unlabelled or only weakly labelled by ubiquitin antibodies. No ubiquitinated structures were seen in neurones from corresponding areas in aged controls. Identification of ubiquitinated proteins in neurodegenerative disorders may provide insights into molecular events associated with cell death.Supported by the Medical Research Council, The Wellcome Trust, and Medical Research Committee of St George's Hospital Medical School, and the Parkinson's Disease Society of Great Britain     

Tau aggregates and tau pathology

There is controversy in some neurodegenerative disorders whether the presence of aberrant aggregates in a neuron could have a toxic or a protective effect. In some disorders like in encephalopathies (prion disease), protein aggregates are toxic for the neuron. In other disorders, like Huntington disease, a protective role has been suggested for the aggregates of huntingtin. In this paper, we review the role of tau aggregation and hypothesize that tau aggregates could have an insufficient protective role in damaged neurons.     

Tau aggregation and toxicity in tauopathic neurodegenerative diseases

Since its discovery as a structural component of neurofibrillary lesions of Alzheimer's disease more than twenty years ago, tau protein has been implicated in the cascade of events associated with neurodegeneration. Specifically, the "tau hypothesis" posits that misfunction of tau, which occurs in response to unknown stimuli, results in its intracellular assembly into filaments that eventually prove toxic to the cells that produce them. The tau hypothesis is supported by numerous neuropathological and genetic observations of authentic human disease cases. However, experiments designed to study aggregate toxicity in biological models suggest that some aggregate species may be inert or could potentially serve a neuroprotective function. Distinguishing these possibilities experimentally has been complicated by currently available biological models, which do not fully recapitulate aggregation conditions seen in disease. Additional model systems which better approximate physiological conditions may help elucidate the molecular mechanisms involved in aggregation associated toxicity. Here we examine the accumulated evidence linking aggregation and neurodegeneration, and experimental approaches to the problem of tau aggregation-mediated toxicity.     

Tau neurofibrillary pathology and microtubule stability

We previously reported that nonomolar concentrations of Taxol and several structurally diverse microtubule (MT)-stabilizing agents significantly enhanced the survival of neurons in the presence of fibrils of amyloid beta peptide (Abeta). Pretreatment of neurons with MT-stabilizing drugs also blocked Abeta-induced activation of tau hyperphosphorylation. Although tau is a substrate for several kinases, we initially focused on cdk5, as this tau kinase has been shown to be activated in Abeta-treated neurons and Alzheimer's disease (AD) brain. In an in vitro kinase assay, Taxol inhibited activation of cdk5 by Abeta. In addition, the proposed cellular cascade in which calpain activation leads to cleavage of the cdk5 regulator, p35, to the strong kinase activator p25 was also prevented. Taxol did not directly inhibit the activity of either cdk5 or calpain, indicating that other cellular components are required for the effect of the drug on Abeta activation of tau phosphorylation. Our results suggest that drugs that interact with MTs can alter signaling events in neurons, possibly because some MTs play a role in organizing protein complexes involved in responses to Abeta. Thus the cytoskeletal network may serve as a biosensor of cellular well-being.     

Cognition and movement in neurodegenerative disorders:a dynamic duo

<正>People with neurodegenerative disorders often experience problems across a variety of functional domains,including cognition,movement,and psychosocial functioning.The classification of these disorders is based on the phenotypical manifestations that represent the most prominent clinical features.For example,Parkinson’s disease and Huntington’s disease are typically regarded as movement disorders,whereas Alzheimer’s disease(AD) and other dementias are regarded as cognitive disorders.     

Sleep in neurodegenerative disorders

Neurodegenerative disorders are a group of heterogeneous, progressive disorders of varying etiology that affect one or more systems. They occur predominantly at older age, during which the structure and amount of sleep undergo changes. Neurodegenerative processes cause structural changes of the sleep/wake generators in the brainstem which result in disorders such as daytime sleepiness, insomnia, sleep-related movement and breathing disturbances, and disorders of the circadian rhythms. Some sleep disorders manifest years before the onset of neurodegenerative disorders and may serve as predictors. Polysomnography shows sleep fragmentation, tonic or phasic movements of the extremities, alteration of respiratory muscles, reduced slow wave sleep, REM sleep absence or without muscle atonia, increased arousal or wake activity, epileptiform EEG activity, and changes in sleep-related breathing. Very frequently, REM sleep behaviour disorder is associated with neurodegenerative disorders. In this overview we present symptoms, pathophysiology, and polysomnographic findings of sleep disorders in prevalent neurodegenerative disorders.     

Physiology and pathology of the blood-brain barrier: implications for microbial pathogenesis, drug delivery and neurodegenerative disorders

The blood-brain barrier (BBB) regulates the passage of solutes between the CNS and the blood. The BBB not only restricts the entry of serum proteins into the CNS, but it also controls the passage of nutrients, electrolytes, vitamins, minerals, free fatty acids, peptides, and regulatory proteins in both the brain to blood and blood to brain direction. The BBB performs these functions through a number of saturable and non-saturable mechanisms. For example, efflux (CNS to blood) mechanisms regulate the levels of nutrients and minerals in the CSF, detoxify the CNS, reinforce the impermeability of the BBB against circulating toxins and many drugs, secrete CNS-originating substances into the blood, and drain substances directly into the cervical lymphatic nodes. Influx mechanisms control the homeostatic environment of the CNS, supply the brain with nutrients, and help to integrate CNS and peripheral functions. These mechanisms are altered in and can be the basis for disease and many of these systems are altered in neuroAIDS. We review here examples of several diseases in which the functions of the BBB are altered, and some conditions, such as alcoholism, multiple sclerosis, obesity, and a subtype of mental retardation, where those altered functions may underlie the pathophysiology. Finally, we consider some of the ways in which these aspects of the BBB could be active in neuroAIDS, including the efflux of anti-virals, the transport of virus by adsorptive endocytosis, egress routes for HIV-1 via brain lymphatics, and the release of neurotoxins from brain endothelial cells.