The keratin cytoskeleton in liver diseases

The keratin intermediate filament (IF) cytoskeleton of hepatocytes has continuously gained medical relevance over the last two decades. Originally it was mainly recognized as a differentiation marker for diagnostic purposes in pathology. However, keratin IFs were soon identified as major cellular structures to be affected in a variety of chronic liver diseases, such as alcoholic and non-alcoholic steatohepatitis (ASH, NASH), copper toxicosis, and cholestasis. Based on observations in keratin gene knock-out mice, the insight into the functional role of keratins was extended from a mere structural role providing mechanical stability to hepatocytes, to an additional role as target and modulator of toxic stress and apoptosis. The functional relevance of keratins in human diseases has recently been underlined by the identification of mutations in keratin genes in patients with liver cirrhosis.     

Inflammation in neurodegenerative diseases

Summary Neurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous system, is the primary pathological feature of acute and chronic neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury and multiple sclerosis. Despite different triggering events, a common feature is chronic immune activation, in particular of microglia, the resident macrophages of the central nervous system. Apart from the pathogenic role of immune responses, emerging evidence indicates that immune responses are also critical for neuroregeneration. Here, we review the impact of innate and adaptive immune responses on the central nervous system in autoimmune, viral and other neurodegenerative disorders, and discuss their contribution to either damage or repair. We also discuss potential therapies aimed at the immune responses within the central nervous system. A better understanding of the interaction between the immune and nervous systems will be crucial to either target pathogenic responses, or augment the beneficial effects of immune responses as a strategy to intervene in chronic neurodegenerative diseases.     

The role of dendritic cells in neurodegenerative diseases

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) involved in the induction of adaptive immune responses. The presence of DCs in the central nervous system (CNS) and the active participation of the immune system in a variety of neurodegenerative diseases have been demonstrated. This review will discuss recent findings pertinent to DCs and other antigen-presenting cells in the CNS in health and disease states.     

The neuropathology of neurodegenerative diseases causing dementia

The dementia syndrome is increasing in prevalence throughout the developed world as the population ages. For example, in the United States it is estimated that between 2000 and 2020, the number of people living to 100 years or more will increase by over 200%, and the number of people surviving to 90–95 years will double. Based on these and other epidemiologic data, the prevalence of diseases causing the dementia syndrome has and will continue to increase dramatically over the next several decades. Considering Alzheimer's disease alone, the most common cause of dementia in the elderly, there are currently 5.5 million persons affected in the United States, and that prevalence will increase to 16 million by the first half of this century. This review will focus on the histopathology of important neurodegenerative diseases of the brain that cause dementia, including Alzheimer's disease, frontotemporal lobar degenerations, and dementia with Lewy bodies. In addition, a less common but extraordinarily interesting condition, chronic traumatic encephalopathy, will be reviewed.     

昼夜节律因子在神经退行性疾病中作用的研究进展

随着人类寿命的增加以及人口老龄化程度的加深,神经退行性疾病发病率逐年升高,严重威胁着人类的健康。目前神经退行性疾病常常存在发病机制不清、有效治疗手段较少、发病进程不可逆等特征。而生理昼夜节律作为维持生物体日常生命活动以及体内稳态的重要调节因素,受昼夜节律因子的调节,其失调可导致神经退行性疾病相关致病蛋白的积累、诱导相关致病激素的异常分泌,进而加重疾病的发病进程。本文围绕阿尔茨海默症(AD)、帕金森症(PD)和亨廷顿舞蹈症(HD)等常见的神经退行性疾病,论述昼夜节律因子调控神经退行性疾病的研究进展,以期为相关疾病发病机制以及干预治疗提供新的视角。     

The use of proteomics in biomarker discovery in neurodegenerative diseases

Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, beta-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both beta-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-beta-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.     

Biomarker-based dissection of neurodegenerative diseases

The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies.     

神经营养因子与神经元退行性变疾病

神经元退行性变疾病包括多种疾病,如常见的老年性痴呆（alzheimer’s disease,AD）和帕金森病（parkinson disease,PD）等。此类疾病的共同特点是进行性的神经元损伤。由于发病机制复杂,并涉及许多至今未知的因素,目前尚无有效的干预措施,故阐明神经元退行性变疾病的发生机制十分重要。神经营养因子（neurotrophic factors,NTFs）是一类调节神经系统发育、成熟和维持神经元功能的天然蛋白质,在神经系统的发生、发育、营养、存活及损伤后修复中起重要作用,是神经元存活和发挥功能的基础。因此,本文主要讨论NTFs与神经元退行性变疾病特别是AD和PD之间的关系。     

脑老化与神经系统退变性疾病

一般认为正常人或健康的脑老化现象,脑的结构与功能已发生病变,与出现以个体行为和认知能力等异常为基本临床表现的神经系统退变性疾病是两个相互独立现象。但是,已有许多证据表明,二者具有相互重叠的临床和神经病理特征、相似的生化改变和病因与发病机制。因此,现在有人认为,脑老化可能是神经系统退变性疾病的最初级阶段,与疾病的发生有着相同的基础。对它的认识,可为神经系统退变性疾病的治疗提出新的思路。本文拟对此作一介绍。     

The "somatic-spread" hypothesis for sporadic neurodegenerative diseases

The major neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis) share in common a mostly sporadic occurrence, a focal onset of pathology, and spread from the initial site of injury to adjacent regions of the nervous system. The sporadic nature and focal onset of these diseases can be explained either by somatic mutations (arising in either of two models of cell lineage) or environmental agents, both of which affect a small number of neurons. The genetic or environmental agent then changes the conformation of a vital protein in these neurons. Spread of the diseases occurs by the misfolded proteins being transferred to adjacent neurons. Clinical and pathological details of one neurodegenerative disorder, amyotrophic lateral sclerosis, are presented to show how the pathogenesis of a typical neurodegenerative disease can be explained by this “somatic-spread” hypothesis. Ultrasensitive techniques will be needed to detect the initiating genetic or environmental differences that are predicted to be present in only a few cells.     

Olfactory dysfunction in aging and neurodegenerative diseases

Alterations in olfactory functions are proposed to be early biomarkers for neurodegeneration. Many neurodegenerative diseases are age-related, including two of the most common, Parkinson’s disease (PD) and Alzheimer’s disease (AD). The establishment of biomarkers that promote early risk identification is critical for the implementation of early treatment to postpone or avert pathological development. Olfactory dysfunction (OD) is seen in 90% of early-stage PD patients and 85% of patients with early-stage AD, which makes it an attractive biomarker for early diagnosis of these diseases. Here, we systematically review widely applied smelling tests available for humans as well as olfaction assessments performed in some animal models and the relationships between OD and normal aging, PD, AD, and other conditions. The utility of OD as a biomarker for neurodegenerative disease diagnosis and future research directions are also discussed.     

MicroRNAs (miRNAs) in neurodegenerative diseases

Aging-related neurodegenerative diseases (NDs) are the culmination of many different genetic and environmental influences. Prior studies have shown that RNAs are pathologically altered during the inexorable course of some NDs. Recent evidence suggests that microRNAs (miRNAs) may be a contributing factor in neurodegeneration. miRNAs are brain-enriched, small ( approximately 22 nucleotides) non-coding RNAs that participate in mRNA translational regulation. Although discovered in the framework of worm development, miRNAs are now appreciated to play a dynamic role in many mammalian brain-related biochemical pathways, including neuroplasticity and stress responses. Research about miRNAs in the context of neurodegeneration is accumulating rapidly, and the goal of this review is to provide perspective for these new data that may be helpful to specialists in either field. An overview is provided about the normal functions for miRNAs, including some of the newer concepts related to the human brain. Recently published studies pertaining to the roles of miRNAs in NDs--including Alzheimer's disease, Parkinson's disease and triplet repeat disorders-are described. Finally, a discussion is included with theoretical syntheses and possible future directions in exploring the nexus between miRNA and ND research.     

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

Reelin is a conserved extracellular glycoprotein crucial for neurodevelopment. In adulthood, Reelin is an important modulator of NMDA receptor-mediated neurotransmission, required for synaptic plasticity, learning and memory. Consequently, abnormal Reelin-mediated signaling has been associated with many human brain disorders involving directly or indirectly altered NMDA receptor function. For most neurological and neuropsychiatric disorders, abnormalities during brain development appear central in the disease etiology. However, a similar causative relationship for neurodegenerative diseases, like Alzheimer's disease (AD), has not been investigated yet.     

Mitochondrial DNA--related mitochondrial dysfunction in neurodegenerative diseases

Mitochondrial dysfunction occurs in several late-onset neurodegenerative diseases. Determining its origin and significance may provide insight into the pathogeneses of these disorders. Regarding origin, one hypothesis proposes mitochondrial dysfunction is driven by mitochondrial DNA (mtDNA) aberration. This hypothesis is primarily supported by data from studies of cytoplasmic hybrid (cybrid) cell lines, which facilitate the study of mitochondrial genotype-phenotype relationships. In cybrid cell lines in which mtDNA from persons with certain neurodegenerative diseases is assessed, mitochondrial physiology is altered in ways that are potentially relevant to programmed cell death pathways. Connecting mtDNA-related mitochondrial dysfunction with programmed cell death underscores the crucial if not central role for these organelles in neurodegenerative pathophysiology. This review discusses the cybrid technique and summarizes cybrid data implicating mtDNA-related mitochondrial dysfunction in certain neurodegenerative diseases.     

Neurogenesis in aging and age-related neurodegenerative diseases

Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aβ, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.     

Transgenic zebrafish models of neurodegenerative diseases

Since the introduction of the zebrafish as a model for the study of vertebrate developmental biology, an extensive array of techniques for its experimental manipulation and analysis has been developed. Recently it has become apparent that these powerful methodologies might be deployed in order to elucidate the pathogenesis of human neurodegenerative diseases and to identify candidate therapeutic approaches. In this article, we consider evidence that the zebrafish central nervous system provides an appropriate setting in which to model human neurological disease and we review techniques and resources available for generating transgenic models. We then examine recent publications showing that appropriate phenotypes can be provoked in the zebrafish through transgenic manipulations analogous to genetic abnormalities known to cause human tauopathies, polyglutamine diseases or motor neuron degenerations. These studies show proof of concept that findings in zebrafish models can be applicable to the pathogenic mechanisms underlying human diseases. Consequently, the prospects for providing novel insights into neurodegenerative diseases by exploiting transgenic zebrafish models and discovery-driven approaches seem favorable.