Hasan Umaira, Jain Himangini, Ali Ruhi
Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), DPSRU, Pushp Vihar, New Delhi, 110017, India.
Curr Drug Targets. 2025 Jun 24. doi: 10.2174/0113894501388678250618070927.
Alzheimer's disease (AD), the most common form of dementia, is a major global health issue. Its complex pathology, including amyloid-beta (Aβ) aggregation, leads to neuronal damage and cognitive decline. Since Aβ plays a major role in AD, therapies targeting its production, aggregation, and clearance are being actively explored. This review discusses recent advances in gene therapy, enzyme inhibitors, molecular modeling, and nano-delivery systems aimed at modifying AD progression, highlighting their potential and challenges.
This review compiles findings on BACE1 and γ-secretase inhibitors, gene therapies that modify amyloid metabolism, and combination therapies. Studies have been selected based on their focus on Aβ regulation and their impact on disease progression, cognitive function, and breakthroughs in diagnostics, molecular modeling, and drug delivery for neurodegenerative conditions.
BACE1 inhibitors, such as verubecestat, and γ-secretase inhibitors, shows potential, however, they face significant challenges related to BBB penetration and adverse effects. Gene therapies using AAV vectors and CRISPR/Cas9 technologies are promising, particularly for individuals genetically predisposed to these diseases. Combination therapies targeting amyloid, tau, and neuro-inflammation have emerged as effective approaches. Advancements in PET, SPECT, MRI, small molecule probes, molecular modeling, and nano-particle-based drug delivery are improving diagnostic and treatment options.
The findings emphasize the multifactorial complexity of amyloid disorders and the limitations of mono-therapies. While certain agents demonstrated efficacy in early disease stages, most treatments have failed in advanced phases due to poor central nervous system (CNS) bioavailability, adverse effects, or insufficient target engagement. Novel delivery systems, combination therapies, and computational design approaches offer enhanced translational potential. However, challenges such as immune responses, delivery efficiency, and off-target effects continue to pose significant barriers.
Aβ-targeted therapies, including enzyme inhibitors and gene therapies, hold promise, though challenges such as BBB penetration and toxicity still remain. Combination therapies, along with advancements in diagnostics and drug delivery technology, are essential for finding effective treatments for Alzheimer's, Parkinson's, and other neurodegenerative diseases. Future research should prioritize overcoming the persistent barriers to BBB penetration, enhancing therapeutic selectivity, and refining drug delivery systems to enable more precise, targeted interventions, to ultimately reduce the progression of disease at the molecular level.
阿尔茨海默病（AD）是痴呆最常见的形式，是一个重大的全球健康问题。其复杂的病理过程，包括β淀粉样蛋白（Aβ）聚集，导致神经元损伤和认知能力下降。由于Aβ在AD中起主要作用，针对其产生、聚集和清除的治疗方法正在积极探索中。本综述讨论了旨在改变AD病程的基因治疗、酶抑制剂、分子建模和纳米递送系统的最新进展，突出了它们的潜力和挑战。
本综述汇编了关于β-分泌酶1（BACE1）和γ-分泌酶抑制剂、改变淀粉样蛋白代谢的基因治疗以及联合治疗的研究结果。所选研究基于其对Aβ调节的关注及其对疾病进展、认知功能以及神经退行性疾病诊断、分子建模和药物递送方面突破的影响。
BACE1抑制剂（如Verubecestat）和γ-分泌酶抑制剂显示出潜力，然而，它们面临与血脑屏障穿透和不良反应相关的重大挑战。使用腺相关病毒（AAV）载体和CRISPR/Cas9技术的基因治疗很有前景，特别是对于有这些疾病遗传易感性的个体。针对淀粉样蛋白、tau蛋白和神经炎症的联合治疗已成为有效的方法。正电子发射断层扫描（PET）、单光子发射计算机断层扫描（SPECT）、磁共振成像（MRI）、小分子探针、分子建模和基于纳米颗粒的药物递送方面的进展正在改善诊断和治疗选择。
研究结果强调了淀粉样蛋白疾病的多因素复杂性以及单一疗法的局限性。虽然某些药物在疾病早期阶段显示出疗效，但由于中枢神经系统（CNS）生物利用度差、不良反应或靶点参与不足，大多数治疗在疾病晚期阶段失败。新型递送系统、联合治疗和计算设计方法具有更大的转化潜力。然而，免疫反应、递送效率和脱靶效应等挑战仍然构成重大障碍。
以Aβ为靶点的治疗方法，包括酶抑制剂和基因治疗，具有前景，尽管血脑屏障穿透和毒性等挑战仍然存在。联合治疗以及诊断和药物递送技术的进步对于找到治疗阿尔茨海默病、帕金森病和其他神经退行性疾病的有效方法至关重要。未来的研究应优先克服血脑屏障穿透的持续障碍，提高治疗选择性，并改进药物递送系统，以实现更精确、有针对性的干预，最终在分子水平上减缓疾病进展。
