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<p>Alzheimer’s disease (AD) is increasingly understood as a disorder of disrupted proteostasis in which chronic failure of the ubiquitin–proteasome system and autophagy-lysosomal pathway allow pathogenic proteins such as tau and Aβ to accumulate and drive neurodegeneration. Against this backdrop, proteolysis-targeting chimeras (PROTACs) offer a mechanistically distinct, event-driven strategy that co-opts E3 ligases to catalytically clear disease-relevant proteins, expanding the druggable space beyond classical enzyme active sites to include tau, GSK-3β, and PI3K/AKT/mTOR signaling nodes. Preclinical studies, including tau degraders such as C004019 that produce sustained (~ 50%) tau reduction with concomitant synaptic and cognitive rescue in AD mouse models, now validate targeted protein degradation as a viable approach to rebalancing neuronal proteostasis in vivo. Building on this emerging evidence, the present review integrates mechanistic and in vivo data on PROTACs in AD, maps the evolving patent and innovation landscape, and critically examines unresolved barriers, including high molecular weight, blood-brain barrier (BBB) penetration, proteasome dysfunction, and off-target risks. We further outline future design principles and translational strategies, including brain-selective E3 ligases, long-acting and nanotechnology-enabled delivery platforms, rational combinations with autophagy modulators or immunotherapies, and stage-specific deployment, that could enable PROTACs to evolve from experimental tools into truly disease-modifying therapies for AD.</p>

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Proteolysis targeting chimeras (PROTAC) for targeting Alzheimer’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月27日

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  • Archna Singh,
  • Anjna Rani,
  • Avijit Mazumder

摘要

Alzheimer’s disease (AD) is increasingly understood as a disorder of disrupted proteostasis in which chronic failure of the ubiquitin–proteasome system and autophagy-lysosomal pathway allow pathogenic proteins such as tau and Aβ to accumulate and drive neurodegeneration. Against this backdrop, proteolysis-targeting chimeras (PROTACs) offer a mechanistically distinct, event-driven strategy that co-opts E3 ligases to catalytically clear disease-relevant proteins, expanding the druggable space beyond classical enzyme active sites to include tau, GSK-3β, and PI3K/AKT/mTOR signaling nodes. Preclinical studies, including tau degraders such as C004019 that produce sustained (~ 50%) tau reduction with concomitant synaptic and cognitive rescue in AD mouse models, now validate targeted protein degradation as a viable approach to rebalancing neuronal proteostasis in vivo. Building on this emerging evidence, the present review integrates mechanistic and in vivo data on PROTACs in AD, maps the evolving patent and innovation landscape, and critically examines unresolved barriers, including high molecular weight, blood-brain barrier (BBB) penetration, proteasome dysfunction, and off-target risks. We further outline future design principles and translational strategies, including brain-selective E3 ligases, long-acting and nanotechnology-enabled delivery platforms, rational combinations with autophagy modulators or immunotherapies, and stage-specific deployment, that could enable PROTACs to evolve from experimental tools into truly disease-modifying therapies for AD.