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This chapter reviews recent work illustrating the utilization of human cortical neurons for the study of molecular mechanisms of β-amyloid (Aβ) and tau-related neuronal degeneration relevant to Alzheimer's disease (AD). It shows that the emerging view of multiple Aβ species capable of deleterious effects at multiple levels co-existing in AD will require a refined therapeutic strategy to address Aβ-mediated neurotoxicity. A specific and complex pattern of tau isoform expression has been observed in human cortical neurons (HCN), which may play a critical role in the development of human tauopathies.

This chapter focuses on the link between correct mitochondrial function and the function of the plasma membrane ion channels and receptors, especially K_ATPM channels, P2x₇ channels, and Ca_v 1.3 Ca²⁺ channels that control the firing of the nigral dopamine (DA) cells and consequently their survival. The roles of the nicotinic, adenosine A_2A, and neurotensin receptors in these neurodegenerative processes are discussed. How an understanding of these molecular mechanisms may lead to the development of novel neuroprotective strategies or to differential treatment for the various types of PD due to their partially overlapping pathogenetic mechanisms is also addressed.

This chapter discusses some of the neurobiological characteristics of the aging dog brain. Aged canines develop signs of neuronal, white matter, and vascular degeneration as observed in human brain aging. Cortical atrophy, white matter degeneration, cerebrovascular dysfunction, and neuron loss may be due to progressive Aβ, tau phosphorylation, and oxidative damage accumulation. Neurodegeneration in the canine brain may form the basis for observations of cognitive decline in multiple domains, including learning and memory.

Multiple sclerosis (MS) is considered an autoimmune chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal damage. The view of MS as a “two-stage disease”, with a predominant inflammatory demyelination in the early phase (relapsing-remitting MS form) and a subsequent secondary neurodegeneration in the early phase (secondary or primary progressive MS) of the disease, is now challenged by the demonstration that axonal destruction may occur independently of inflammation and may also produce it. Therefore, as CNS inflammation and degeneration can coexist throughout the course of the disease, MS may be a “simultaneous two-component disease”, in which the combination of neuroinflammation and neurodegeneration promotes irreversible disability. This chapter discusses factors that contribute to the pathogenesis of MS, immune surveillance in the CNS, regulation of immune responses in the inflamed CNS, initiation of T helper 1 (Th1)-mediated immune reactions in the inflamed CNS, amplification of Th1-mediated immune responses in inflamed CNS and tissue damage, and development of autoimmunity in MS.

This chapter examines the role of cytokines in neurodegeneration, considering the methodological approaches and evidence for their contribution, likely mechanisms of expression and action, and clinical relevance. It discusses the synthesis of cytokine in neurodegenrative conditions, neuroprotective effects of cytokines, neurotoxic actions of cytokines, and mechanisms of cytokine involvement in neurotoxicity. The chapter also provides a diagram showing cytokine involvement in acute neurodegeneration.

Cytokine is the term used to describe a large and expanding group or family of polypeptides which can be synthesized by most cell types, and influence numerous biological processes. Recent research indicates that cytokines have diverse effects on nervous system function and have been implicated in various forms of neurological disease and injury. However, the emerging picture is a complex one, and cytokines have been proposed as both mediators and inhibitors of neuronal survival and death. Some of this complexity arises from the varied experimental approaches employed, the absence of suitable inhibitors or receptor antagonists for many cytokines, and the wide range of doses, concentrations, bioactivity and origin of the cytokines used. In order to establish a biological role for any cytokine in neurodegeneration, it is necessary to demonstrate its synthesis in an appropriate temporal and spatial manner, the effects of the cytokine at relevant concentrations, and that inhibition of its action modifies neurodegeneration. This chapter reviews the methods which have been used and are now becoming available to achieve these aims. It summarizes known mechanisms of neurodegeneration in order to facilitate discussion of possible sites of cytokine action.

Alzheimer's disease (AD) is a relentlessly progressive dementing disorder with an incidence that increases very sharply with age. Of the many potential bases for neurodegeneration in AD, immune-directed attack is one of the most easily conceived because such processes are inherently destructive. Typically, this destruction is beneficial to the host, as in the warding off of extrinsic pathogens. Sometimes it is not, as in autoimmune diseases. This chapter describes evidence that there is a prominent immune response in AD. Particular attention is given to the autodestructive forces that are inherent to such a response, and the potential harm they can cause. The possibility of ameliorating such damage through the use of anti-inflammatory drugs is discussed.

Excitoxic damage, metabolic imbalance, oxidative stress, and calcium influx are each capable of inducing cell death by both necrotic and apoptotic mechanisms. If these various mechanisms contribute, separately and together, to neurodegeneration, then a rational strategy for treatment must be to search for ways of blocking the individual components of the cascade that leads to death. One of the major events in the cycle of excitotoxicity and cell death is the influx of calcium, and the consequent imbalance of intracellular homeostasis leading to cell death. This is particularly true in stroke, where calcium imbalance has been seen to provide an important component in the development and spread of the penumbral damage.

Frontotemporal lobar degeneration (FTLD) is a syndrome of focal, often asymmetric, neurodegeneration presenting clinically as a progressive dementia associated with focal atrophy of the frontal and/or temporal lobes. The disease is capable of producing striking changes in personality, behaviour, and language, with a diverse range of clinical presentations. Two major clinical presentations of FTLD are recognized. In the frontal variant — usually designated frontotemporal dementia (FTD) — the emergence of disinhibition, mental rigidity, stereotyped and perseverative behaviour, hyperorality, and loss of insight give rise to marked changes in personality. An aphasic variant — designated primary progressive aphasia (PPA) — is also recognized. The fluent variant appear to have difficulty expressing and understanding meaning, a syndrome that has been given the name semantic dementia (SD). In contrast, the nonfluent variant — progressive nonfluent aphasia (PNFA). Because FTLD can be associated with degeneration of cortical and bulbar motor neurons and anterior horn cells of the spinal cord, some patients with FTD, SD, or PNFA also meet clinical criteria for amyotrophic lateral sclerosis (ALS).

Alzheimer's disease (AD) represents one neurodegenerative disorder whose etiology remains unknown. Animal model systems for AD are further hampered by the absence of the tools necessary to duplicate some of the known neurodegenerative changes. For example, slow progressive neurodegeneration has been difficult to reproduce. The studies presented in this chapter were conducted to determine whether the neurochemical deficits noted in AD could produce some of the cognitive symptoms of AD in animals, and whether the cognitive deficits so produced would be amenable to pharmacological alleviation. Based on these investigations, the chapter shows that some of the neurochemical deficits noted in AD may be intimately linked to another hallmark of the AD brain, namely, the synthesis of β-amyloid precursor protein.

Recent studies suggest that, at least under neurodegenerative conditions, local brain formation of estradiol by the enzyme aromatase is an endogenous neuroprotective mechanism. This chapter reviews neuroprotective actions of aromatase and local estradiol synthesis in different experimental models of brain pathology in mammals. The cell types involved in the production of aromatase after brain injury, the role of neurogenesis and synaptic plasticity in the mechanisms of neuroprotection, the consequences of aromatase deficiency for brain function, and the possible implication of brain aromatase in the generation of sex differences in brain pathology are also discussed.

In the avian brain, aromatase is constitutive and inducible in neurons and glia respectively. Glial aromatase is rapidly and dramatically upregulated in astroglia (astrocytes and radial glia) independent of brain region, in response to perturbation of the neuropil. Estrogens, synthesized by induced aromatization in glial cells, are potent mitigators of apoptotic degeneration and may accelerate neuronal replacement following brain damage. Specifically, aromatase inhibition increases, and estradiol replacement decreases secondary degeneration at the site of primary damage in the passerine brain. Indeed, the characteristic wave of secondary degeneration observed in mammals following compromise of the brain, is severely dampened in the passerine brain and is only revealed following inhibition of inducible glial aromatization. Further, the rate of injury-induced neurogenesis is increased in birds receiving estradiol replacement relative to those treated with an aromatase inhibitor alone. This chapter reviews data on the structural and functional consequences of glial aromatization. It highlights emerging data on the signals that invariably accompany brain damage and their potential role as inductive signals for the transcription and translation of the aromatase gene specifically in glial cells. The robust and cell-specific expression of aromatase in the passerine brain continues to provide an excellent model for the study of the provision of estrogens to neural targets with temporal and spatial specificity. In addition to basic scientific questions, passerine songbirds may serve as superb animal models toward understanding clinical syndromes involving brain damage, ischemia/anoxia, and neurodegeneration.

This chapter is concerned with the results of studies performed with neurophysiological techniques. Their integration with flow/metabolic methods constitutes, at present, the best way to evaluate plasticity in the normal and abnormal human brain as represented by three paradigmatic conditions: healthy aging, neurodegeneration, and ischemic stroke. It concentrates on neurophysiological correlates of cortical plasticity. This chapter shows that since, both in healthy aging and in different models of disease, neuroplasticity is an efficient way to maintain brain function despite progressive loss of its resources, deepening the knowledge on the mechanisms regulating cerebral function and plastic phenomena might prompt newer and more efficacious therapeutic and rehabilitative strategies for neurologic diseases.

This chapter describes the connection between the nerve growth factor (NGF) and Alzheimer’s disease (AD). It reveals that NGF can be considered as an anti-amyloidogenic factor that normally keeps the amyloidogenic pathway under control. It states that the experimental study of AD11 neurodegeneration exhibited a novel causal connection between neurotrophic signaling deficits and Alzheimer’s neurodegeneration. This chapter shows the therapeutic potential of the painless NGF molecules, displaying full neurotrophic activity and reduced pain-related signaling capability.

As life expectancy increases, burden of illness soars. The growing magnitude of the health problem and numerous failed trials of agents once considered worth investment (e.g., Alzheimer, Parkinson, and Huntington diseases) demand critical examination. Neurodegeneratives diseases are more complicated than previously thought, and assumptions based on imperfect or incomplete information from animal models are flawed. There is, however, renewed optimism that science will be able to provide relief. This chapter considers existing scientific gaps in effective treatments for neurodegeneration. Discoveries that present tantalizing therapeutic hypotheses are viewed as pieces of a puzzle. At its core, neurodegeneration is a problem of cell health. Importantly, cells are interrelated within the brain, and thus study cannot be limited to one type of cell. Neurodegenerative diseases must be considered as disorders of nervous system circuits, with patients’ symptoms manifestations of neural circuit dysfunction. Successful treatment needs to normalize the biology within individual cells and tissue, and preserve or repair the information processing in important neural circuits. This places new biologic discoveries in perspective and promotes discussion of gaps that stand between discoveries and knowledge of neurodegeneration in overall tissues and circuit dysfunction that eventuates clinically.

This chapter focuses on the neuroprotective properties of phytocannabinoids, beginning with a description of those cellular and molecular mechanisms and signaling pathways underlying these properties (e.g., control of glutamate homeostasis, calcium influx, toxicity of reactive oxygen species, glial activation, inflammatory events, and others). This is followed by descriptions of studies conducted with phytocannabinoids either in preclinical models of acute neurodegeneration, that focus particularly on ischemia, brain trauma, and spinal injury, or in preclinical models of certain chronic progressive neurodegenerative disorders, that focus particularly on Huntington’s chorea, Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. The chapter also discusses those neurodegenerative disorders that are presently being subjected to clinical phytocannabinoid research.

Glaucoma, diabetic retinopathy, age-related macular degeneration, and intraocular inflammation (uveoretinitis) are the major causes of blindness in developed countries. Although different diseases are caused by different reasons, oxidative stress and inflammation are known to be the key detrimental factors. Cannabinoids have both antioxidant and anti-inflammatory functions, and may have therapeutic potential in these sight-threatening conditions. This chapter discusses current understandings about the role of (endo)cannabinoids in the pathogenesis of these degenerative and inflammatory retinal conditions. The chapter further explores the therapeutic potential of phytocannabinoids in different eye conditions and the challenges that we are facing. Additional research that might facilitate the exploitation of phytocannabinoids as medicines for managing these sight-threatening ocular diseases is also briefly discussed in the chapter.

Structural magnetic resonance imaging (MRI) is a powerful tool to visualize and quantitate morphological and pathological features of the aging brain. Most work that has used structural MRI to study Alzheimer’s disease (AD) focused on the spatial distribution of atrophic changes associated with disease. These studies consistently show focal atrophy beginning in medial temporal lobes in early and presymptomatic stages of AD before spreading globally throughout the cortical mantle. Normal cognitive aging—aging in the absence of major neurodegenerative disease—on the other hand follows and anterior-to-posterior gradient of atrophic change. In addition to atrophic changes, conventional structural MRI can be used to appreciate markers of small and large vessel cerebrovascular disease, including white matter hyperintensities (WMHs), cerebral microbleeds, and infarction. Studies that have examined cerebrovascular changes associated with AD also show a consistent relationship with risk and severity of clinical AD, particularly with regard to lobar microbleeds and posterior WMH. It is unclear whether cerebrovascular changes play an independent role in the clinical expression of AD or whether it is more mechanistically related, reflecting a core feature of the disease. This chapter reviews recent work on regional atrophy in AD and normal aging, as well as work on small and large cerebrovascular disease in AD.

Countering the traditional emphasis on loss that dominates much of the neurological literature, some authors have recently chosen to focus on the positive changes that may accompany neurological diseases. This paradoxical facilitation of certain functions attests to the complexity, plasticity and compensatory capacity of the human brain. Specifically, there are rare cases of dementia patients whose art gains greater critical acclaim as their disease progresses. Studies of these patients inform both the neuroscience of creativity, and the aspects of art that are appreciated by specialists and the general public. An overview of the different clinical syndromes is followed by a review of both group and case studies of patients who have been shown to continue to create art in the setting of dementia. This review is followed by a discussion of how findings from these patients are reconciled with the more popular theories regarding the brain basis of creativity.

In recent decades, there has been a more critical examination of the Nazi past within German and Austrian neuroscience. The Spiegelgrund euthanasia brains and brain parts in Vienna were finally buried by 2012 and victims were commemorated. More anonymous brain burials occurred in Munich and Tübingen in the early 1990s, which likely did not adequately commemorate victims and, furthermore, a recent comprehensive investigation of all brain specimens held by the Max Planck Society is underway. The Hugo Spatz Prize was renamed by the German Neurological Society, but the Heinrich Pette Prize still exists. This society and another have laudably conducted investigations leading to publications about Nazi-era neuroscience, but much work must still be done. Additionally, Hallervorden–Spatz disease has largely been renamed, but other collaborator eponyms remain in use and raise the question of what response the neuroscience community should take toward these, and toward experimental data from Nazi-era investigations.