Baron Rona, Harpaz Idan, Nemirovsky Anna, Cohen Hagit, Monsonego Alon
Department of Microbiology and Immunology and National Institute of Biotechnology in Negev, Faculty of Health Sciences, Ben-Gurion University of Negev, PO Box 653, Beer-Sheva 84105, Israel.
Exp Gerontol. 2007 Jan-Feb;42(1-2):64-9. doi: 10.1016/j.exger.2006.07.001. Epub 2006 Oct 30.
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by memory loss and severe cognitive decline. The etiology of the disease has not been explored, although a significant body of evidence suggests that neuronal dysfunction is caused by hyperphosphorylation and intracellular accumulation of the Tau protein, extracellular accumulation of the amyloid beta-peptide (Abeta), and the associated chronic activation of glial cells. Clearance of toxic Abeta, apoptotic cells and debris from the brain together with induction of neuronal repair mechanisms may all take place partially throughout the progression of AD, but therapeutic approaches based on knowledge of these processes have been unsuccessfully developed. Here, we address the question of whether autoimmune mechanisms can be boosted to safely facilitate the above-mentioned clearance and neuronal repair in the AD brain. We have previously demonstrated that depending on genetic background, autoimmunity targeted to Abeta is already induced in elderly individuals and in patients with AD. We have shown in a mouse model of AD that given a preexisting proinflammatory milieu in the brain, immune cells can enter the brain tissue and participate in clearance of Abeta. Furthermore, the decline in cognitive functions and neurogenesis throughout the progression of AD may also be affected by autoimmune mechanisms operating in the periphery and in the brain. In light of the so-far unsuccessful anti-inflammatory approaches to treating AD, we suggest that boosting - rather than suppressing - the endogenous immune mechanisms induced in AD may enhance repair pathways in the brain, provided that this approach can be safely applied.
阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，其特征为记忆丧失和严重的认知衰退。尽管大量证据表明，神经元功能障碍是由Tau蛋白的过度磷酸化和细胞内积累、淀粉样β肽（Aβ）的细胞外积累以及相关的胶质细胞慢性激活所引起，但该疾病的病因尚未得到充分探究。在AD的整个病程中，清除大脑中的有毒Aβ、凋亡细胞和碎片以及诱导神经元修复机制可能都会部分发生，但基于对这些过程的了解所开发的治疗方法均未成功。在此，我们探讨是否可以增强自身免疫机制，以安全地促进AD大脑中的上述清除和神经元修复。我们之前已经证明，根据遗传背景，针对Aβ的自身免疫在老年人和AD患者中已经被诱导。我们在AD小鼠模型中表明，鉴于大脑中预先存在的促炎环境，免疫细胞可以进入脑组织并参与Aβ的清除。此外，在AD病程中认知功能和神经发生的下降也可能受到外周和大脑中运行的自身免疫机制的影响。鉴于迄今为止治疗AD的抗炎方法均未成功，我们建议增强而非抑制AD中诱导的内源性免疫机制可能会增强大脑中的修复途径，前提是这种方法可以安全应用。
