Department of Neurology, Johns Hopkins Bayview Medical Center, USA.
Annu Rev Neurosci. 2011;34:185-204. doi: 10.1146/annurev-neuro-061010-113613.
Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.
阿尔茨海默病（AD）是全球痴呆症的主要病因，其特征是大脑中β-淀粉样肽（Aβ）的积累，以及微管相关蛋白 tau 的过度磷酸化和裂解形式。遗传、生化和行为研究表明，神经毒性 Aβ肽从淀粉样前体蛋白（APP）的顺序蛋白水解中生理产生是 AD 发展的关键步骤。APP 是一种单次跨膜蛋白，在大脑中表达水平较高，通过一系列连续的蛋白酶（包括跨膜 γ-分泌酶复合物）以快速和高度复杂的方式代谢，该复合物还可加工其他关键调节分子。为什么 Aβ会在老年人的大脑中积累尚不清楚，但可能与 APP 代谢或 Aβ清除的变化有关。从 APP 加工的生化和遗传研究中获得的经验教训对于开发治疗 AD 的治疗靶点至关重要。
