Brain Research Reviews最新文献

Almost a quarter of a century ago, interleukin-6 (IL-6) was discovered as an inflammatory cytokine involved in B cell differentiation. Today, IL-6 is recognized to be a highly versatile cytokine, with pleiotropic actions not only in immune cells, but also in other cell types, such as cells of the central nervous system (CNS). The first evidence implicating IL-6 in brain-related processes originated from its dysregulated expression in several neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. In addition, IL-6 was shown to be involved in multiple physiological CNS processes such as neuron homeostasis, astrogliogenesis and neuronal differentiation.

The molecular mechanisms underlying IL-6 functions in the brain have only recently started to emerge. In this review, an overview of the latest discoveries concerning the actions of IL-6 in the nervous system is provided. The central position of IL-6 in the neuroinflammatory reaction pattern, and more specifically, the role of IL-6 in specific neurodegenerative processes, which accompany Alzheimer's disease, multiple sclerosis and excitotoxicity, are discussed. It is evident that IL-6 has a dichotomic action in the CNS, displaying neurotrophic properties on the one hand, and detrimental actions on the other. This is in agreement with its central role in neuroinflammation, which evolved as a beneficial process, aimed at maintaining tissue homeostasis, but which can become malignant when exaggerated. In this perspective, it is not surprising that ‘well-meant’ actions of IL-6 are often causing harm instead of leading to recovery.

The purpose of this article is to review the recent developments of abnormal mitochondrial dynamics, mitochondrial fragmentation, and neuronal damage in neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The GTPase family of proteins, including fission proteins, dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1), and fusion proteins (Mfn1, Mfn2 and Opa1) are essential to maintain mitochondrial fission and fusion balance, and to provide necessary adenosine triphosphate to neurons. Among these, Drp1 is involved in several important aspects of mitochondria, including shape, size, distribution, remodeling, and maintenance of mitochondria in mammalian cells. In addition, recent advancements in molecular, cellular, electron microscopy, and confocal imaging studies revealed that Drp1 is associated with several cellular functions, including mitochondrial and peroxisomal fragmentation, phosphorylation, SUMOylation, ubiquitination, and cell death. In the last two decades, tremendous progress has been made in researching mitochondrial dynamics, in yeast, worms, and mammalian cells; and this research has provided evidence linking Drp1 to neurodegenerative diseases. Researchers in the neurodegenerative disease field are beginning to recognize the possible involvement of Drp1 in causing mitochondrial fragmentation and abnormal mitochondrial dynamics in neurodegenerative diseases. This article summarizes research findings relating Drp1 to mitochondrial fission and fusion, in yeast, worms, and mammals. Based on findings from the Reddy laboratory and others', we propose that mutant proteins of neurodegenerative diseases, including AD, PD, HD, and ALS, interact with Drp1, activate mitochondrial fission machinery, fragment mitochondria excessively, and impair mitochondrial transport and mitochondrial dynamics, ultimately causing mitochondrial dysfunction and neuronal damage.

Representing the most common cause of dementia, Alzheimer's disease (AD) has dramatically impacted the neurological and economic health of our society. AD is a debilitating neurodegenerative disease that produces marked cognitive decline. Much evidence has accumulated over the past decade to suggest soluble oligomers of beta-amyloid (Aβ) have a critical role in mediating AD pathology early in the disease process by perturbing synaptic efficacy. Here we critically review recent research that implicates synapses as key sites of early pathogenesis in AD. Most excitatory synapses in the brain rely on dendritic spines as the sites for excitatory neurotransmission. The structure and function of dendritic spines are dynamically regulated by cellular pathways acting on the actin cytoskeleton. Numerous studies analyzing human postmortem tissue, animal models and cellular paradigms indicate that AD pathology has a deleterious effect on the pathways governing actin cytoskeleton stability. Based on the available evidence, we propose the idea that a contributing factor to synaptic pathology in early AD is an Aβ oligomer-initiated collapse of a “synaptic safety net” in spines, leading to dendritic spine degeneration and synaptic dysfunction. Spine stabilizing pathways may thus represent efficacious therapeutic targets for combating AD pathology.

The modest effects of neurotrophic factor (NTF) treatment on lifespan in both animal models and clinical studies of Amyotropic Lateral Sclerosis (ALS) may result from any one or combination of the four following explanations: 1.) NTFs block cell death in some physiological contexts but not in ALS; 2.) NTFs do not rescue motoneurons (MNs) from death in any physiological context; 3.) NTFs block cell death in ALS but to no avail; and 4.) NTFs are physiologically effective but limited by pharmacokinetic constraints. The object of this review is to critically evaluate the role of both NTFs and the intracellular cell death pathway itself in regulating the survival of spinal and cranial (lower) MNs during development, after injury and in response to disease. Because the role of molecules mediating MN survival has been most clearly resolved by the in vivo analysis of genetically engineered mice, this review will focus on studies of such mice expressing reporter, null or other mutant alleles of NTFs, NTF receptors, cell death or ALS-associated genes.

Demyelinating diseases are characterized by an extensive loss of oligodendrocytes and myelin sheaths from axolemma. These neurological disorders are a common cause of disability in young adults, but so far, there is no effective treatment against them. It has been suggested that neural stem cells (NSCs) may play an important role in brain repair therapies. NSCs in the adult subventricular zone (SVZ), also known as Type-B cells, are multipotential cells that can self-renew and give rise to neurons and glia. Recent findings have shown that cells derived from SVZ Type-B cells actively respond to epidermal-growth-factor (EGF) stimulation becoming highly migratory and proliferative. Interestingly, a subpopulation of these EGF-activated cells expresses markers of oligodendrocyte precursor cells (OPCs). When EGF administration is removed, SVZ-derived OPCs differentiate into myelinating and pre-myelinating oligodendrocytes in the white matter tracts of corpus callosum, fimbria fornix and striatum. In the presence of a demyelinating lesion, OPCs derived from EGF-stimulated SVZ progenitors contribute to myelin repair. Given their high migratory potential and their ability to differentiate into myelin-forming cells, SVZ NSCs represent an important endogenous source of OPCs for preserving the oligodendrocyte population in the white matter and for the repair of demyelinating injuries.

Neuronal dysfunctions and neurodegeneration are often associated with defects in membrane transport. Synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathological feature — insoluble aggregates composed largely of the protein α-synuclein in certain populations of neurons and glia. The actual physiological function of the brain-enriched α-synuclein is still not particularly clear. What is obvious is that when the protein is present in pathologically high amounts, or in mutant forms with enhanced membrane association and oligomerization, it causes neuronal demise with manifestations of impaired neuronal traffic, heightened oxidative stress, mitochondrial degeneration and defects in lipid metabolism. α-synuclein's direct association with the activities of key components of the eukaryotic membrane traffic machinery, namely Rabs and the soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptors (SNAREs), has highlighted a key role for membrane transport defects in α-synuclein-mediated pathology. Here, we summarize and discuss recent findings in this regard, and their implications in the molecular aspects of synucleinopathy.

Spinal cord injuries in mammals, including humans, have devastating long-term consequences. Despite substantial research, therapeutic approaches developed in mammalian model systems have had limited success to date. An alternative strategy in the search for treatment of spinal cord lesions is provided by regeneration-competent vertebrates. These organisms, which include fish, urodele amphibians, and certain reptiles, have a spinal cord very similar in structure to that of mammals, but are capable of spontaneous structural and functional recovery after spinal cord injury. The present review aims to provide an overview of the current status of our knowledge of spinal cord regeneration in one of these groups, teleost fish. The findings are discussed from a comparative perspective, with reference to other taxa of regeneration-competent vertebrates, as well as to mammals.

The majority of research on functional cerebral lateralization in primates revolves around vocal abilities, addressing the evolutionary origin of the human language faculty and its predominance in the left hemisphere of the brain. Right hemisphere specialization in spatial cognition is commonly reported in humans. This functional asymmetry is especially evident in the context of the unilateral neglect, a deficit in attention to and awareness of one side of space, that more frequently occurs after right-side rather than left-side brain damage. Since most of the research efforts are concentrated on vocalization in primates, much less is known about the presence or absence of spatial functions lateralization. Obtaining this knowledge can provide insight into the evolutionary aspect of the functionally lateralized brain of Homo sapiens and deliver refinement and validation of the nonhuman primate unilateral neglect model. This paper reviews the literature on functional brain asymmetries in processing spatial information, limiting the search to nonhuman primates, and concludes there is no clear evidence that monkeys process spatial information with different efficiency in the two hemispheres. We suggest that lateralization of spatial cognition in humans represents a relatively new feature on the evolutionary time scale, possibly developed as a by-product of the left hemisphere intrusion of language competence. Further, we argue that the monkey model of hemispatial neglect requires reconsideration.