Exploring LRP-1 in the liver-brain axis: implications for Alzheimer's disease

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.