Abstract
Alzheimer’s disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. AZ7235, a previously discovered Axl kinase inhibitor, was identified to have robust apoE activity in brain microglia, astrocytes and pericytes. AZ7235 also increased expression of ATP-binding cassette protein A1 (ABCA1), which is involved in the lipidation and secretion of apoE. Moreover, AZ7235 did not exhibit Liver-X-Receptor (LXR) activity and stimulated apoE and ABCA1 expression in the absence of LXR. Target validation studies using AXL−/− CCF-STTG1 cells showed that Axl is required to mediate AZ7235 upregulation of apoE and ABCA1. Intriguingly, apoE expression and secretion was significantly attenuated in AXL-deficient CCF-STTG1 cells and reconstitution of Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl also plays a role in maintaining apoE homeostasis in astrocytes independent of its kinase activity. Lastly, these effects may require human apoE regulatory sequences, as AZ7235 exhibited little stimulatory activity toward apoE and ABCA1 in primary murine glia derived from neonatal human APOE3 targeted-replacement mice. Collectively, we identified a small molecule that exhibits robust apoE and ABCA1 activity independent of the LXR pathway in human cells and elucidated a novel relationship between Axl and apoE homeostasis in human astrocytes.
Highlights
Alzheimer’s Disease (AD) is the most common form of dementia
Intraperitoneal administration of an anti-Apolipoprotein E (apoE) antibody into AD mice improves cognitive function and reduces brain amyloid β (Aβ) load [17], and decreasing APOE expression by antisense oligonucleotides significantly alleviates Aβ pathology in amyloid mice homozygous for the APOE3 or APOE4 allele [18]. In both AD patients and AD animal models, apoE4 protein levels are lower in the central nervous system (CNS) compared to the other apoE isoforms [19,20,21,22,23], and decreased cerebrospinal fluid (CSF) apoE levels are associated with reduced CSF Aβ42 and worse clinical outcome, whereas increased CSF apoE has been suggested to be a protective response to injury in AD [24, 25]
The present study was designed to provide new insights into apoE regulation that may lead to novel therapeutic approaches targeting apoE levels and lipidation
Summary
Alzheimer’s Disease (AD) is the most common form of dementia. Apolipoprotein E (ApoE), which is abundantly secreted from astrocytes, microglia, and pericytes, is the major lipid carrier in the brain [1,2,3] and the major genetic risk factor for late-onset AD, which accounts forAs apoE has pleiotropic activities, there is considerable debate about whether raising or lowering apoE leve lsZhao et al Molecular Brain (2020) 13:66 might be beneficial for AD. Intraperitoneal administration of an anti-apoE antibody into AD mice improves cognitive function and reduces brain Aβ load [17], and decreasing APOE expression by antisense oligonucleotides significantly alleviates Aβ pathology in amyloid mice homozygous for the APOE3 or APOE4 allele [18]. In both AD patients and AD animal models, apoE4 protein levels are lower in the central nervous system (CNS) compared to the other apoE isoforms [19,20,21,22,23], and decreased cerebrospinal fluid (CSF) apoE levels are associated with reduced CSF Aβ42 and worse clinical outcome, whereas increased CSF apoE has been suggested to be a protective response to injury in AD [24, 25]. As apoE plays important roles in lipid transport, neuroinflammation, synaptic plasticity and blood brain barrier (BBB) integrity [26,27,28], an overall reduction of apoE levels throughout adulthood is not without risk
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