Cell：李伟/胡宝洋/周琪团队开发靶向蛋白降解新技术SPYTAC，穿越血脑屏障清除Aβ，安全治疗阿尔茨海默病

Core Viewpoint - Alzheimer's disease (AD) affects approximately 57 million people globally and is the leading cause of dementia, with the pathological features being amyloid plaques and neurofibrillary tangles. The accumulation of beta-amyloid (Aβ) is considered a core driver of the disease, leading to a focus on Aβ-targeted therapies for drug development [3][4]. Group 1: Research Findings - Recent clinical trial results indicate that Aβ immunotherapy can slow disease progression in early-stage Alzheimer's by reducing Aβ levels in the brain, although it may cause brain inflammation and amyloid-related imaging abnormalities (ARIA) [3][4]. - A new approach using extracellular targeted protein degradation (eTPD) has been developed, specifically a programmable synthetic peptide-mediated lysosomal targeting chimeric (SPYTAC) platform, which aims to effectively degrade Aβ while minimizing adverse effects [4][5]. Group 2: SPYTAC Platform - SPYTAC utilizes low-density lipoprotein receptor-related protein-1 (LRP1) to facilitate targeted degradation of extracellular proteins and cross the blood-brain barrier (BBB), showing effectiveness in reducing Aβ load in both peripheral and brain tissues in 5×FAD Alzheimer's mouse models [5][9]. - Compared to traditional immunotherapies, SPYTAC demonstrates fewer side effects, including reduced incidence of brain hemorrhage and inflammation, highlighting its potential for safer treatment options [5][11]. Group 3: Advantages and Potential - The modular and gene-encoded nature of SPYTAC allows for targeted customization of pathogenic proteins, showcasing its versatility in treating various diseases driven by pathogenic proteins [5][12]. - The study emphasizes that SPYTAC represents a promising, programmable, and gene-encoded eTPD method with significant potential for clinical translation in Alzheimer's disease [12].