日本科學(xué)家最近發(fā)現(xiàn),，實驗鼠腦組織萎縮前數(shù)月,，一種免疫細胞趨于活躍。如果人腦存在同樣現(xiàn)象,，這一發(fā)現(xiàn)將幫助醫(yī)生提前診斷認知癥等腦萎縮疾病,。  

    日本放射醫(yī)學(xué)綜合研究所的科學(xué)家將成果發(fā)表在最新一期美國《神經(jīng)元》雜志上。他們在論文中介紹說,，通過基因操作,，他們培育出一批實驗鼠。這些老鼠的腦內(nèi)容易積聚一種特殊的蛋白質(zhì),，而這種蛋白質(zhì)過多會導(dǎo)致老鼠患認知癥,。  

    所謂認知癥，就是癡呆癥,。由于“癡呆”一詞含有輕蔑之意,，日本厚生勞動省２００４年１２月正式?jīng)Q定把癡呆癥這一用語改為認知癥,。  

    這次最新的研究表明,，轉(zhuǎn)基因鼠出生后９個月，它們的腦組織開始出現(xiàn)萎縮,。但科學(xué)家們同時發(fā)現(xiàn),，當這些實驗鼠出生后３個月，即腦組織萎縮半年之前,，它們腦內(nèi)的免疫細胞——小膠質(zhì)細胞就已經(jīng)開始活躍起來,。  

    此項研究的負責人樋口真人分析說，特殊的蛋白質(zhì)開始在腦細胞中堆積后,，小膠質(zhì)細胞也會聚集到一起并且趨于活躍,，以求清除堆積的蛋白質(zhì)。他們認為,，如果人腦存在同樣現(xiàn)象,，那么就可以通過觀測小膠質(zhì)細胞的活躍程度，提前診斷認知癥。  

    提前服藥,，對于治療認知癥非常重要,。日本科學(xué)家的研究發(fā)現(xiàn)，如果在實驗鼠出生兩三個月時喂給它們免疫抑制劑,，腦組織的萎縮就可以得到抑制,。

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.

更多英文原文鏈接：http://www.neuron.org/content/article/fulltext?uid=PIIS0896627307000086