抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

https://www.cell.com/cell-metabolism/pdf/S1550-4131(11)00420-7.pdf

Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Alcohol consumption is an integral part of daily life in many societies. The benefits associated with the production, sale, and use of alcoholic beverages come at an enormous cost to these societie...

Alcoholism: a systems approach from molecular physiology to addictive behavior.

https://www.cell.com/neuron/pdf/S0896-6273%2814%2900260-8.pdf

Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders

Orexin (hypocretin) innervation of the paraventricular nucleus of the thalamus.

The shell of the nucleus accumbens (NacSh) receives a dense innervation from dopamine (DA) neurons in the ventral tegmental area (VTA) and from glutamate neurons in the paraventricular nucleus of the thalamus (PVT). The present study examined in urethane-anesthetized rats the effects of electrical stimulation of the PVT on DA levels in the NacSh as measured with amperometry and chronoamperometry. Stimulation of the PVT (40 Hz, 1.0 ms, 400 microA, 5 seconds) resulted in a brief increase in electrochemical currents detected in the NacSh. Inhibition of DA neurons in the VTA using lidocaine (4%, 500 nL) or intravenous apomorphine (0.15 mg/kg) decreased the resting voltammetric signal but had no effect on PVT-evoked responses. Blocking of ionotropic glutamate receptors in the NacSh with local administration of kynurenic acid attenuated the PVT-evoked responses. Anterograde tracing with biotinylated dextran amine demonstrated that PVT targets regions of very dense tyrosine hydroxylase fiber staining in the NacSh. Consistent with the projection pattern of the PVT to the NacSh, stimulation of the PVT evoked the largest oxidation current changes in the NacSh, whereas small or no changes were elicited in other areas of the striatum. This study suggests that glutamate release from PVT terminals can act on ionotropic glutamate receptors in the NacSh to induce DA efflux. Modulation of DA levels in the NacSh by the PVT may be linked to arousal-induced increases in DA tone and could be involved in the facilitation of specific behavioral patterns associated with arousal or stressful situations.

Functional and anatomical connection between the paraventricular nucleus of the thalamus and dopamine fibers of the nucleus accumbens

Active neurons have a high demand for energy substrate, which is thought to be mainly supplied as lactate by astrocytes. Heavy lactate dependence of neuronal activity suggests that there may be a mechanism that detects and controls lactate levels and/or gates brain activation accordingly. Here, we demonstrate that orexin neurons can behave as such lactate sensors. Using acute brain slice preparations and patch-clamp techniques, we show that the monocarboxylate transporter blocker α-cyano-4-hydroxycinnamate (4-CIN) inhibits the spontaneous activity of orexin neurons despite the presence of extracellular glucose. Furthermore, fluoroacetate, a glial toxin, inhibits orexin neurons in the presence of glucose but not lactate. Thus, orexin neurons specifically use astrocyte-derived lactate. The effect of lactate on firing activity is concentration dependent, an essential characteristic of lactate sensors. Furthermore, lactate disinhibits and sensitizes these neurons for subsequent excitation. 4-CIN has no effect on the activity of some arcuate neurons, indicating that lactate dependency is not universal. Orexin neurons show an indirect concentration-dependent sensitivity to glucose below 1 mm, responding by hyperpolarization, which is mediated by ATP-sensitive potassium channels composed of Kir6.1 and SUR1 subunits. In conclusion, our study suggests that lactate is a critical energy substrate and a regulator of the orexin system. Together with the known effects of orexins in inducing arousal, food intake, and hepatic glucose production, as well as lactate release from astrocytes in response to neuronal activity, our study suggests that orexin neurons play an integral part in balancing brain activity and energy supply.

https://www.jneurosci.org/content/jneuro/30/24/8061.full.pdf

ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal.

It has become well accepted that Huntington disease (HD) is associated with impaired glutamate uptake, resulting in a prolonged time-course of extracellular glutamate that contributes to excitotoxicity. However, the data supporting this view come largely from work in synaptosomes, which may overrepresent nerve-terminal uptake over astrocytic uptake. Here, we quantify real-time glutamate dynamics in HD mouse models by high-speed imaging of an intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) and electrophysiological recordings of synaptically activated transporter currents in astrocytes. These techniques reveal a disconnect between the results obtained in synaptosomes and those in situ. Exogenous glutamate uptake is impaired in synaptosomes, whereas real-time measures of glutamate clearance in the HD striatum are normal or even accelerated, particularly in the aggressive R6/2 model. Our results highlight the importance of quantifying glutamate dynamics under endogenous release conditions, and suggest that the widely cited uptake impairment in HD does not contribute to pathogenesis.

Matthew P. Parsons

Papers

Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders

Orexin (hypocretin) innervation of the paraventricular nucleus of the thalamus.

Functional and anatomical connection between the paraventricular nucleus of the thalamus and dopamine fibers of the nucleus accumbens

ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal.

Real-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models