HDL from an Alzheimer's disease perspective

Abstract

Purpose of review: We review current knowledge regarding HDL and Alzheimer's disease, focusing on HDL's vasoprotective functions and potential as a biomarker and therapeutic target for the vascular contributions of Alzheimer's disease.

Recent findings: Many epidemiological studies have observed that circulating HDL levels associate with decreased Alzheimer's disease risk. However, it is now understood that the functions of HDL may be more informative than levels of HDL cholesterol (HDL-C). Animal model studies demonstrate that HDL protects against memory deficits, neuroinflammation, and cerebral amyloid angiopathy (CAA). In-vitro studies using state-of-the-art 3D models of the human blood-brain barrier (BBB) confirm that HDL reduces vascular Aβ accumulation and attenuates Aβ-induced endothelial inflammation. Although HDL-based therapeutics have not been tested in clinical trials for Alzheimer's disease , several HDL formulations are in advanced phase clinical trials for coronary artery disease and atherosclerosis and could be leveraged toward Alzheimer's disease .

Summary: Evidence from human studies, animal models, and bioengineered arteries supports the hypothesis that HDL protects against cerebrovascular dysfunction in Alzheimer's disease. Assays of HDL functions relevant to Alzheimer's disease may be desirable biomarkers of cerebrovascular health. HDL-based therapeutics may also be of interest for Alzheimer's disease, using stand-alone or combination therapy approaches.

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FIGURE 1

Vasoprotective functions of HDL relevant for Alzheimer's disease. HDL has been shown to have at least four distinctive functions that could protect against Alzheimer's disease. HDL suppresses the pathological accumulation of Aβ in cerebral vessels known as cerebral amyloid angiopathy (CAA). HDL suppresses vascular inflammation induced by Aβ or pro-inflammatory cytokines and global neuroinflammation in Alzheimer's disease. HDL stimulates the production of nitric oxide from brain endothelial cells. HDL delays the fibrillization of Aβ. Although large, spherical HDL is unlikely to cross the blood–brain barrier, apoA-I can gain access to the brain via the blood–CSF barrier at the choroid plexus. HDL-like particles in the brain are mainly apoE-based. ApoE is found in three isoforms in humans; apoE2, apoE3, and apoE4. APOε4 is the major genetic risk factor for late-onset Alzheimer's disease and apoE4 has several detrimental functions including delaying Aβ transport out of the brain, promoting blood–brain barrier breakdown, and increasing neuroinflammation. ApoE is also found in the CSF along with apoA-I. Aβ, amyloid beta; apoA-I, apolipoprotein A-I; apoE, apolipoprotein E; BBB, blood–brain barrier; CSF, cerebrospinal fluid; HDL, high-density lipoprotein; LDLR, low-density lipoprotein receptor; LRP-1, low-density lipoprotein receptor-related protein 1.