日本科学家最近发现，实验鼠脑组织萎缩前数月，一种免疫细胞趋于活跃。如果人脑存在同样现象，这一发现将帮助医生提前诊断认知症等脑萎缩疾病。
日本放射医学综合研究所的科学家将成果发表在最新一期美国《神经元》杂志上。他们在论文中介绍说，通过基因操作，他们培育出一批实验鼠。这些老鼠的脑内容易积聚一种特殊的蛋白质，而这种蛋白质过多会导致老鼠患认知症。
所谓认知症，就是痴呆症。由于“痴呆”一词含有轻蔑之意，日本厚生劳动省２００４年１２月正式决定把痴呆症这一用语改为认知症。
这次最新的研究表明，转基因鼠出生后９个月，它们的脑组织开始出现萎缩。但科学家们同时发现，当这些实验鼠出生后３个月，即脑组织萎缩半年之前，它们脑内的免疫细胞——小胶质细胞就已经开始活跃起来。
此项研究的负责人樋口真人分析说，特殊的蛋白质开始在脑细胞中堆积后，小胶质细胞也会聚集到一起并且趋于活跃，以求清除堆积的蛋白质。他们认为，如果人脑存在同样现象，那么就可以通过观测小胶质细胞的活跃程度，提前诊断认知症。
提前服药，对于治疗认知症非常重要。日本科学家的研究发现，如果在实验鼠出生两三个月时喂给它们免疫抑制剂，脑组织的萎缩就可以得到抑制。
Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice
Giovanna R. Mallucci,1, Melanie D. White,1 Michael Farmer,1 Andrew Dickinson,1 Husna Khatun,2 Andrew D. Powell,2 Sebastian Brandner,1 John G.R. Jefferys,2 and John Collinge1
1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
2 Department of Neurophysiology, Division of Neuroscience, University of Birmingham, Birmingham, B15 2TT, United Kingdom
Corresponding author
Summary
Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrPC) (the precursor of its disease-associated isoform, PrPSc) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrPC is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrPSc deposits accumulate and recover rapidly after PrPC depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrPSc. These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.
Introduction
Changes in motivation, mood, and behavior are common early symptoms in human prion disorders, especially variant Creutzfeldt-Jakob disease (vCJD), often occurring long before diagnosis is made. By the time characteristic dementia and motor deficits are established, there is typically advanced neuronal loss, with no realistic potential for curative treatment or recovery. In experimentally infected mice, clinical disease is diagnosed by the presence of locomotor changes, but again, these occur during advanced disease and correspond with irreversible neuronal loss. However, there are earlier pathological and phenotypic changes. Spongiform change and synapse loss precede neuronal loss (Jeffrey et al., 2000), and changes in species-typical behaviors also occur long before typical motor symptoms (Betmouni et al., 1999, Cunningham et al., 2005, Deacon et al., 2001, Guenther et al., 2001) and correlate with early loss of presynaptic terminals in the dorsal hippocampus (Cunningham et al., 2003).
We previously showed that early spongiform degeneration in the hippocampus of prion-infected mice reverses when PrPC is depleted in neurons (Mallucci et al., 2003). We now ask whether this early pathological change produces functional deficits and whether its reversal is reflected in functional recovery. As the hippocampus is particularly targeted by several strains of murine prions and is easily accessible for neurophysiological measurements, we focused on tests of hippocampal function. We used prion-infected transgenic mice with and without “induced” PrP depletion for our experiments. Thus, tg37 mice express PrP from “floxed” PrP sequences (MloxP transgenes) and succumb to Rocky Mountain Laboratory (RML) prion infection ∼13 weeks postinoculation (wpi) (Mallucci et al., 2002). In these mice, earliest prion pathological changes, including spongiosis, gliosis, and PrPSc deposition, appear by 8 wpi (Mallucci et al., 2003). In double-transgenic NFH-Cre/tg37 mice, PrP expression is the same as in tg37 mice until floxed PrP sequences are excised by the DNA recombinase, Cre (Sauer et al., 1989), at ∼9–10 weeks of age, when neuronal PrP is depleted (Mallucci et al., 2002). NFH-Cre/tg37 mice infected with prions at 1 week of age develop early hippocampal pathology in parallel with control tg37 mice, but spongiosis reverses soon after Cre-mediated PrP depletion ∼8–9 wpi, and the animals survive long term (Mallucci et al., 2003).
We tested memory function and spontaneous ethological behaviors in vivo and measured synaptic responses neurophysiologically in vitro. We used the novel object recognition task, a nonspatial learning task based on the spontaneous preference of both mice and rats for novelty and their ability to remember previously encountered objects, that is rapidly learned (Clark et al., 2000, Dodart et al., 1997, Ennaceur et al., 1988, Messier, 1997). In rodents, the hippocampus is thought to be involved in delay-dependent object-recognition memory (i.e., when recognition intervals are long, >24 hr after learning phase), whereas recall over shorter retention intervals is thought to involve parahippocampal structures (Clark et al., 2000, Hammond et al., 2004, Mumby et al., 2005). Novel-object recognition is extensively used for testing declarative memory in mice, and, critically, performance is independent of mouse strain or genetic background, unlike most other memory tasks for which performance is highly strain dependent (Sik et al., 2003). We also tested the spontaneous behaviors of burrowing and nesting, which have a robust association with early prion pathology (Betmouni et al., 1999, Cunningham et al., 2005, Deacon et al., 2001, Guenther et al., 2001) and also localize to the dorsal hippocampus. These behaviors have been proposed as powerful tools for elucidating brain function (Gerlai et al., 1999), requiring a high degree of organization and executive function, and are thought to reflect motivational aspects of spontaneous behavior in rodents.
更多英文原文链接：http://www.neuron.org/content/article/fulltext?uid=PIIS0896627307000086
