Sharma Vivek Kumar
Department of Pharmacology, Govt. College of Pharmacy, Rohru, Shimla, Himachal Pradesh, 171207, India.
Mol Biol Rep. 2025 Sep 8;52(1):873. doi: 10.1007/s11033-025-10980-8.
Alzheimer's disease (AD) is the most common, complex, and untreatable form of dementia which is characterized by severe cognitive, motor, neuropsychiatric, and behavioural impairments. These symptoms severely reduce the quality of life for patients and impose a significant burden on caregivers. The existing therapies offer only symptomatic relief without addressing the underlying silent pathological progression. This therapeutic gap has catalysed interest in alternative pathological pathways, particularly the dysregulation of amyloid-beta (Aβ) homeostasis and associated metabolic dysfunctions. Traditionally viewed as a central nervous system (CNS) disorder, AD is now increasingly understood to involve peripheral organs, notably the liver, which plays a pivotal role in the regulation of systemic and cerebral homeostasis. Emerging evidence highlights the liver's involvement in the clearance of Aβ, as well as in the modulation of oxidative stress, brain energy metabolism, insulin resistance, microtubule dynamics, and neuroinflammation, the key features of AD pathogenesis. Among the hepatic factors implicated, low-density lipoprotein receptor-related protein-1 (LRP-1) is of particular interest. LRP-1 facilitates peripheral Aβ clearance and is also expressed abundantly in key brain regions such as the entorhinal cortex, hippocampus, and cerebellum. Beyond neurons, LRP-1 is localized in activated astrocytes, microglia, and various elements of the neurovascular unit, including brain endothelial cells, vascular smooth muscle cells, pericytes, and the choroid plexus-highlighting its critical role at the blood-brain barrier (BBB). Activation of hepatic LRP-1 has been shown to attenuate key neuropathological processes in AD, including oxidative stress, insulin resistance, tau pathology, neuroinflammation, and apoptosis. These effects not only improve short-term neuronal resilience but also contribute to long-term neuroprotection. Taken together, these findings underscore the significance of the liver-brain axis, positioning hepatic LRP-1 as a central mediator of AD pathology. This review aims to explore the multifaceted role of hepatic LRP-1 in AD progression and proposes it as a novel therapeutic strategy to combat AD.
阿尔茨海默病（AD）是最常见、最复杂且无法治愈的痴呆形式，其特征为严重的认知、运动、神经精神和行为障碍。这些症状严重降低了患者的生活质量，并给护理人员带来了巨大负担。现有的治疗方法仅能缓解症状，无法解决潜在的隐匿性病理进展。这种治疗差距激发了人们对替代病理途径的兴趣，尤其是淀粉样β蛋白（Aβ）稳态失调及相关代谢功能障碍。传统上，AD被视为一种中枢神经系统（CNS）疾病，但现在人们越来越认识到它涉及外周器官，特别是肝脏，肝脏在全身和脑稳态的调节中起着关键作用。新出现的证据表明，肝脏参与Aβ的清除，以及氧化应激、脑能量代谢、胰岛素抵抗、微管动力学和神经炎症的调节，这些都是AD发病机制的关键特征。在涉及的肝脏因素中，低密度脂蛋白受体相关蛋白1（LRP-1）特别受关注。LRP-1促进外周Aβ的清除，并且在关键脑区如内嗅皮质、海马体和小脑中也大量表达。除了神经元，LRP-1还定位于活化的星形胶质细胞、小胶质细胞以及神经血管单元的各种成分，包括脑内皮细胞、血管平滑肌细胞、周细胞和脉络丛，这突出了其在血脑屏障（BBB）中的关键作用。肝脏LRP-1的激活已被证明可减轻AD中的关键神经病理过程，包括氧化应激、胰岛素抵抗、tau病理、神经炎症和细胞凋亡。这些作用不仅能提高短期神经元弹性，还有助于长期神经保护。综上所述，这些发现强调了肝脑轴的重要性，将肝脏LRP-1定位为AD病理的核心介质。本综述旨在探讨肝脏LRP-1在AD进展中的多方面作用，并提出将其作为对抗AD的一种新的治疗策略。
