Alzheimer’s disease (AD) is the leading cause of dementia affecting the elderly in the United States, with as many as 5 million Americans currently diagnosed. The cost to patients and caregivers measures in the billions of dollars, and will increase in the coming decades. As the population ages, developing effective treatments for AD will become even more critical.

One of the ways researchers are trying to treat the disease, is by targeting the lesions which form in the patients’ brains. In AD, there are two major types of lesion, plaques which form outside the cell composed of amyloid-beta peptide and intracellular neurofibrillary tangles composed of highly phosphorylated tau protein.

Much of the focus has been on amyloid plaques; however, research suggests that once symptoms occur, removing the plaques may not stop the progress of the disease. At this stage, it may be better to target tau as its pathology correlates better with the severity of dementia than plaque deposition. Eventually, when the disease can be diagnosed in its earliest stages, both of these hallmark pathologies should be targeted together to attempt to prevent memory impairments.

Active and passive immunotherapy

One promising approach for targeting tau lesions is immunotherapy, in which antibodies are used to bind to the pathological tau protein and promote its clearance. There are two types of immunotherapy, active and passive, which have their own advantages and drawbacks.

由于大多数病理tau蛋白都存在于神经元中，因此最好的治疗抗体可能是可以在细胞内外工作的抗体。

在主动免疫疗法中，给予靶蛋白以及辅助剂以鼓励免疫反应。使用这种类型，人体会产生自己的抗体，效果持久。

However, because in the case of AD this would mean eliciting an immune response against a protein that naturally occurs in the brain, there is a greater risk of side effects than with the passive approach.

In passive immunotherapy, the patient is given antibodies that are generated in a laboratory. The effects will last only as long as the antibodies remain in the patient’s system, meaning that they will not be permanent.

但是，使用这种方法副作用的风险降低了，然后每月向患者提供大约一次的抗体可能对感兴趣的蛋白质具有很高的特异性。

曾经认为，使用对像TAU这样的细胞内蛋白质的治疗抗体是不可能的，但是两个关键发现表明这些假设是错误的。首先，几个组表明，神经元（主要受TAU病理学影响的脑细胞）可以从细胞外液中吸收抗体。

Second, the tau protein has been shown to be released from cells and to be taken up by neighboring cells, which may lead to spread of the pathology throughout the brain. These findings indicate two ways in which antibodies could be used against tau pathology: 1) for intracellular clearance and 2) to block the spread by binding to tau outside the cell.

研究抗体功效

In our most recent study, we tested the efficacy of two different tau antibodies, recognizing a similar site of the tau protein, in transgenic mice and cell culture models. In the animals, one of these antibodies reduced soluble pathological tau and improved memory. We then assessed whether these antibodies could prevent tau toxicity and its spread in cultured neurons using tau purified from an Alzheimer’s patient.

这些结果表明，额外的和细胞内机制都在发挥有效的免疫疗法。

我们的结果表明，作用机理取决于添加抗体时的病理TAU的位置。当我们同时将两者添加到培养的细胞中，而大多数tau是细胞外的，抗体与细胞外的tau结合，并防止其被吸收并对细胞产生毒性作用。但是，当tau后24小时添加抗体时，抗体进入神经元并细胞内中和tau蛋白，以防止其毒性。

这些结果表明，细胞外机制都在开发有效的免疫疗法方面发挥作用。尽管我们的小组和其他人已经观察到与有益作用相关的神经元摄取的抗体摄取，但其他实验室的抗体已经看到了可能仅在细胞外部起作用的抗体。由于大多数病理tau蛋白都存在于神经元中，因此最好的治疗抗体可能是可以在细胞内外工作的抗体。

令人惊讶的结果

我们发现的有趣之处在于，有效抗体与大多数tau蛋白的紧密结合不如无效抗体。进一步的研究表明，它的功效可以通过其与从人脑分离的tau蛋白的可溶性形式的强大结合来解释。

These results indicate that strong binding to various forms of the target protein does not predict efficacy and this should be taken into account for development of this approach for clinical trials.