Schmitt H Peter
Institute of Pathology, Department for Neuropathology, University of Heidelberg, Germany.
Med Hypotheses. 2007;69(3):596-609. doi: 10.1016/j.mehy.2007.01.022. Epub 2007 Mar 6.
The aetiology of Alzheimer's disease (AD) and the transmissible spongiform encephalopathies (tSEs) is still elusive. The concept that prion protein (PrP(Sc)) is the aetiological agent (infectious protein) in the tSEs has recently been questioned. In AD, the cause of the aberrant cleavage of the beta-amyloid precursor protein (APP), resulting in the production of amyloidogenic Abeta fragments, has yet remained obscure. Moreover, the amyloid hypothesis of AD has been seriously challenged. In both AD and the tSEs, pathogens of various nature, including bacteria, have been discussed as possible causal factors. However, aetiological considerations have completely neglected microbial products such as the bacterial toxic proteins (BTPs). The present paper is aimed at drawing a "culprit profile" of these toxic molecules that can exert, at low-dosage, neuro-degeneration through various effects. Clearly, BTPs may affect cell-surface receptors including modulatory amine transmitter receptor expression, block neuro-transmitter release, increase intra-cellular Ca(2+) levels, affect intra-cellular signal transduction, change cyto-skeletal processing, alter synaptic transmission, influence APP proteolysis, interact with cell surface proteins like PrP(C) or their GPI anchors, act as chaperones inducing conformational change in proteins (e.g., PrP(C) to PrP(Sc)), alter lipid membrane integrity by affecting phospholipases or forming pores and channels, induce vacuolar (spongiform) change and elicit inflammatory reactions with cytokine production including cytokines that were demonstrated in the AD brain. Like PrP(Sc), BTPs can be heat-stable and acid-resistant. BTPs can meet the key-proteins of AD and tSEs in the lipid-rich domains of the plasma membrane called rafts. Basically, this might enable them to initiate a large variety of unfavourable molecular events, eventually resulting in pathogenetic cascades as in AD and the tSEs. All in all, their profile lends support to the hypothesis that BTPs might represent relevant culprits capable to cue and/or promote neuro-degeneration in both AD and the tSEs.
阿尔茨海默病（AD）和传染性海绵状脑病（tSEs）的病因仍然不明。朊病毒蛋白（PrP(Sc)）是tSEs病因（感染性蛋白）的这一概念最近受到了质疑。在AD中，β淀粉样前体蛋白（APP）异常切割导致淀粉样生成性Aβ片段产生的原因仍不清楚。此外，AD的淀粉样蛋白假说也受到了严重挑战。在AD和tSEs中，包括细菌在内的各种性质的病原体都被讨论为可能的致病因素。然而，病因学方面的考虑完全忽略了诸如细菌毒性蛋白（BTPs）等微生物产物。本文旨在勾勒出这些毒性分子的“罪魁祸首特征”，它们能够通过各种作用在低剂量下引发神经退行性变。显然，BTPs可能会影响细胞表面受体，包括调节性胺类递质受体的表达，阻断神经递质释放，增加细胞内Ca(2+)水平，影响细胞内信号转导，改变细胞骨架加工过程，改变突触传递，影响APP蛋白水解，与细胞表面蛋白如PrP(C)或其糖基磷脂酰肌醇锚相互作用，作为伴侣蛋白诱导蛋白质构象改变（如PrP(C)转变为PrP(Sc)），通过影响磷脂酶或形成孔道来改变脂质膜完整性，诱导空泡（海绵状）改变并引发炎症反应，产生细胞因子，包括在AD大脑中已被证实的细胞因子。与PrP(Sc)一样，BTPs可以耐热且耐酸。BTPs可以在质膜富含脂质的区域即脂筏中与AD和tSEs的关键蛋白相遇。基本上，这可能使它们引发各种各样不利的分子事件，最终导致如AD和tSEs中那样的致病级联反应。总而言之，它们的特征支持了这样一种假说，即BTPs可能是在AD和tSEs中引发和/或促进神经退行性变的相关罪魁祸首。
