Targeting Alzheimer's Disease: The Critical Crosstalk between the Liver and Brain

Abstract

Alzheimer's disease (AD), an age-related neurodegenerative disorder, is currently incurable. Imbalanced amyloid-beta (Aβ) generation and clearance are thought to play a pivotal role in the pathogenesis of AD. Historically, strategies targeting Aβ clearance have typically focused on central clearance, but with limited clinical success. Recently, the contribution of peripheral systems, particularly the liver, to Aβ clearance has sparked an increased interest. In addition, AD presents pathological features similar to those of metabolic syndrome, and the critical involvement of brain energy metabolic disturbances in this disease has been recognized. More importantly, the liver may be a key regulator in these abnormalities, far beyond our past understanding. Here, we review recent animal and clinical findings indicating that liver dysfunction represents an early event in AD pathophysiology. We further propose that compromised peripheral Aβ clearance by the liver and aberrant hepatic physiological processes may contribute to AD neurodegeneration. The role of a hepatic synthesis product, fibroblast growth factor 21 (FGF21), in the management of AD is also discussed. A deeper understanding of the communication between the liver and brain may lead to new opportunities for the early diagnosis and treatment of AD.

Keywords: Alzheimer’s disease; amyloid-beta; fibroblast growth factor 21 (FGF21); liver; low-density lipoprotein receptor-related protein-1 (LRP-1).

Figure 1

The potential communication between liver dysfunction and AD neurodegeneration. Under normal physiological conditions (left), hepatocytes uptake circulating Aβ via LRP-1 and promote Aβ clearance. FGF21 can also be processed by the liver, and then delivered to the brain via the blood, where it can exert protective effects. Circulating FGF21 may contribute to the stability of the astrocyte–neuron–lactate shuttle system and cerebral energy homeostasis. Under pathological conditions (right), diminished LRP-1 hinders hepatic Aβ clearance, and the liver’s ability to synthesize FGF21 may also be compromised, leading to reduced supplementation of these substances to the brain. Although it is not yet clear what drives the impaired astrocyte–neuron–lactate shuttle system in AD and whether there is a causal relationship between that and liver dysfunction, lower FGF21 may weaken its protective effect on this communication system. Additionally, normal glucose regulation in the liver is essential for maintaining systemic glucose homeostasis. Conversely, compromised hepatic glucose regulation may induce hyperglycemia and disrupt glucose metabolism in the brain.