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 Wysłany: Wto 7:44, 26 Kwi 2011 Temat postu: Alzheimer disease and apoptosis _138 |
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Alzheimer disease and apoptosis
Alzheimer disease (AD) is associated with autosomal 1 (1q31-42/STM22), 14 (14q24.3/S182), 19 (ApoE) and 21 (App21m sites) defects and neuronal loss in neurodegenerative lesions. Lack of effective treatment, AD in developed countries has become the heart disease, cancer and stroke, after the fourth human death. The clinical disease is characterized by recent memory and intellectual functions of the deterioration. Neuropathology in the cerebral cortex and hippocampus is characterized by a large number of inflammatory plaques in elderly (senile plaque, SP) and neurofibrillary tangles (neurofibrilary tangle, NFT), and the accompanying loss of neurons. To the mechanism of disease in terms of, AD seems to be a more causes, involving a variety of pathological mechanisms and the emergence of a variety of pathological manifestations of the In recent years many data indicate that immune and inflammatory mechanisms in AD, plays an important role in the development of [1 3]. McGeer and Rodgers AD first proposed the neural degeneration may be the brain of chronic immune and inflammatory responses the result of inappropriate activation, superior immune response may be . Present the view that cell death can be divided into two categories, one is from a variety of sudden, unexpected event caused by cell death, that is, pathological cell death, morphologically manifested as cell death (necrosis); another Class of rational living cell death, also known as programmed cell death (programmed cell death, PCD), morphology showed apoptosis (apoptosis). Generally speaking, excessive apoptosis, can cause degeneration or premature death. Hippocampal neurons of AD patients in TRPM-2 RNA expression is an expression of neuronal apoptosis. Recent experimental evidence suggests that: Apoptosis is aging and AD and other neurodegenerative diseases, neuronal loss of one of the reasons, internal and external factors that activate the cell's own genetic program causing neuronal apoptosis. 1 neuronal apoptosis in chronic inflammation hypothesis recent years, immunohistochemical studies have shown that many neurological diseases, especially AD patients have a strong focal brain inflammation, tissue culture and molecular biological methods has proved a lot of brain cells to produce inflammatory cytokines (eg IL-1β, IL-6, TNF-α, TGF-β, etc.), complement proteins and other immune molecules. These inflammatory proteins and small glial cells (microglia, Mi) activation with the close relationship between AD lesions that have been proposed neuronal degeneration of the inflammation hypothesis. In recent years, on β-amyloid protein (amyloid protein β, A β) activation of immune and inflammatory process indirectly the hypothesis of neurodegenerative diseases get a lot of new evidence. AD patients with brain macromolecules and insoluble Aβ class extracellular NFTs, can easily be found in phagocytic cells, and thus as a chronic irritant substances gradually accumulate and stimulate inflammation continue to strengthen, resulting in chronic inflammation of AD status. AD many of the precipitating factors such as heredity, age, environmental factors can induce the initial lesion (such as AD, SP and NFT), these lesions even if the cause of death of some neurons, but also relatively minor, and thus slow disease; However, these initial lesions can stimulate inflammation, which developed to a certain extent, have resulted in more neuronal death, causing more lesions, and thus stimulate more severe inflammatory response, and so form a continuously strengthened its toxicity Circle (autotoxic loop). This positive feedback loop leads to the observed clinical AD and similar progress of the disease in the initial stage of more moderate, to a sharp deterioration in the period before the disease. Thus, chronic inflammation may be a necessary factor in AD pathogenesis. AD is the Aβ deposition around the Mi by activating the nervous system production of cytokines and inflammatory immune response, accelerated neuronal cell death that may cause memory loss and cognitive impairment diseases. The memory and temporal lobe activity in hippocampal CA1 neurons, suggesting that the pathogenesis of AD Aβ may start CA1 neurons and other cells. 2 neuronal apoptosis induced apoptosis (PCD) genes controlled by an active cell death process, specific genes for various reasons Erzhi DNA encoding a suicide protein cleavage. More and more evidence that most animal cells Jieneng self to death, and this universal suicide program can signal from the other cells from the bottom of the activation or inhibition. For example, many developing vertebrate neuronal survival depends on the target cells connected neurotrophic factor (NTF), if the NTF can be caused by a lack of neurogenesis in PCD. PCD cells is also affected by exogenous factors, but induced PCD of endogenous and exogenous factors must play a role of specific genes. 2.1 neurotoxicity of amyloid protein and is growing evidence that, Aβ is induced by a variety of reasons common pathway AD, AD is a key factor in the formation and development [5]. Molecular cloning studies have shown that, Aβ from a molecular weight greater β-amyloid precursor protein (β-amyloid precursor protein, APP). At present, most scholars believe, Aβ accumulation in the cerebral cortex is the process of AD pathogenesis in an early bound event, ahead of other brain damage and clinical symptoms for several years [6]. In the event of the order, Aβ early appearance of neurofibrillary tangles and axonal pathological changes such as lack of nutrition and clinical symptoms. The most direct evidence of Aβ under certain conditions is able to show neurotoxicity. The early 90s, Yankner and other first observed higher concentrations of Aβ can cause neuronal degeneration and death, and confirmed that the essential structure of toxicity caused by 25 to 35 of its amino acid sequence (Aβ25 ~ 35). Recently discovered, Aβ neurotoxicity involves two aspects [7], first, to enhance or enlarge a variety of noxious stimuli such as sugar, excitement, toxins, free radicals, cell damage effects, one direct cellular toxicity. It was found that the majority of cells can be in contact with Aβ showed cell swelling, chromatin condensation, nuclear DNA breakage in the typical apoptotic morphology and biochemical characteristics [8], only a few cells or co-exist with excitement when the toxin neurons showed swelling, membrane lysis, lactate dehydrogenase release and other necrosis (necrosis) features [9]. Aβ neurotoxicity involves complex molecular mechanisms, including promotion of free radical formation, destruction of intracellular Ca2 + homeostasis [7], reduce the K + channel function [10], increased proinflammatory cytokines (cytokine) inflammation caused by reaction [11]. Because of a variety of factors interact to bring about a considerable difficulty. 2.2 of inflammatory cytokines and nerve poison 2.2.1 interleukin 6 (IL-6): in the central nervous system (CNS), IL -6 mainly by Mi and astrocytes (astrocyte, As) production, its receptor is also widely present in the hypothalamus, hippocampus, cortex and other brain neurons membrane. IL-6 toxicity of neurons mainly in the brain of transgenic mice was confirmed. Campbell [12] reported, IL-6 transgenic mice with severe neurological symptoms of the disease, manifested as thin, abnormal behavior, tremors, ataxia and epilepsy. Neuropathological characteristics, hippocampus and cerebellum apparent neuronal degeneration, especially in hippocampal area CA1 dendritic atrophy, vacuolation of dendrites and dendritic decrease in the number, and accompanied by high expression of IL-6 mRNA and high levels of IL -6. These results suggest that brain levels of IL-6 transgenic mice led to increased neuronal degradation. In addition IL-6 transgenic mouse study also found that across a function of hippocampal cholinergic pathway severely damaged [13], because every one pathway involved in hippocampal formation of memory imprinting, so high levels of IL-6 in brain may affect learning and memory function. on IL-6 and the relationship of Aβ or the APP has been reported [14]. In primary cultured rat cortical neurons experiments, IL-6 200 ng / mL and 6 h after exposure of neurons, APP mRNA expression was increased by about double. Because IL-6 and APP or Aβ in SP coexist in AD, suggests that IL-6 对 APP has a direct regulation of the expression, can promote APP production, leading to Aβ deposition, induced AD. α2-M is known to most protease inhibitors, and IL-6 co-exist in the AD cortex and hippocampus SP. Been reported [15], in cultured human neuronal cell lines,[link widoczny dla zalogowanych], α2-M could inhibit the normal secretion of APP, leading to increased Aβ formation. In human SH-SY5Y neuronal cell cultures, α2-M of the basis for synthesis of very low, but after stimulation with IL-6 was strongly induced the synthesis, α2-M levels increased by approximately 20-fold [16]. These results suggest, IL-6 and α2-M in AD brain the coexistence of functional linkages, IL-6 may be through induction of α2-M synthesis, thereby inhibiting the normal hydrolysis APP, leading to an abnormal increase in Aβ generation and deposition, thereby induced AD pathogenesis. 2.2.2 tumor necrosis factor-α (TNF-α): LPS can stimulate Mi produce TNF-α, As may also have a small amount of TNF-α. In human fetal neurons in primary culture was found, TNF-α can enhance the N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity [17], and human neuronal cells HN33. 1 has cytotoxic effect. Nerve cell culture, TNF-α played by acting on the cell toxicity of As indirect neuronal damage caused. TNF-α directly injected into the mouse cerebellum, which can cause general damage. TNF-α can cause Mi cattle and rodents play through the mechanism of cytotoxicity of PCD. However, this role has not been found yet in humans. 2.2.3 of transforming growth factor-β (TGF-β): TGF-β is a multifunctional role of cytokines, it can be a variety of cells in the embryonic stage nerve cells occurred and immune and inflammatory response during the development process, TGF-β has an important role. Rat neocortical nerve cell culture
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