Influence of APOE genotypes on blood brain barrier transport of DHA by mfsd2a in Alzheimer's Disease

APOE基因型对阿尔茨海默病中mfsd2a血脑屏障转运DHA的影响

• 批准号: 10515657
• 负责人: Laila Abdullah
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515657
• 关键词: Address; Affect; Afghanistan; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Animals; Antiinflammatory Effect; Apolipoprotein E; Astrocytes; Biological Availability; Blood; Blood - brain barrier anatomy; Brain; Cerebrovascular system; Chronic; Circulation; Data; Dementia; Development; Diagnosis; Disease; Docosahexaenoic Acids; Encephalitis; Environment; Exposure to; Extracellular Matrix; Gelatinase B; General Population; Genes; Genotype; High Prevalence; Human; Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Integral Membrane Protein; Investigation; Iraq; Lecithin; Life; Lipids; Lysophosphatidylcholines; Mediating; Membrane; Microglia; Mus; Neurofibrillary Tangles; Nuclear; Omega-3 Fatty Acids; Patients; Pattern; Pericytes; Peripheral; Peroxisome Proliferator-Activated Receptors; Plasma; Play; Population; Post-Traumatic Stress Disorders; Protein Isoforms; Proteins; Resistance; Risk; Role; Senile Plaques; Signal Pathway; Signal Transduction; Soldier; Therapeutic; Transgenic Mice; Traumatic Brain Injury; Up-Regulation; Veterans; War; Work; apolipoprotein E-4; blood-brain barrier function; brain endothelial cell; brain parenchyma; combat injury; cytokine; dietary; experience; genetic risk factor; high risk; high risk population; improved; in vivo; lipid transport; military veteran; mouse model; neuroinflammation; neurotransmission; pharmacologic; pre-clinical; prevent; repaired; uptake; β-amyloid burden

Over 200,000 US Veterans are suffering from Alzheimer's disease (AD) and this figure is expected to increase dramatically in the next few decades due to a higher prevalence of traumatic brain injury (TBI) and post- traumatic stress disorder (PTSD) that are risk factors of AD among soldiers returning from Iraq and Afghanistan wars. The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk factor for AD, representing 60% of AD subjects in the general population. The apoE protein is a functional component of plasma involved in the transport of docosahexaenoic acid (DHA) into the brain which plays a key role in neurotransmission, membrane repair and cell signaling. Recent investigations have identified loss of DHA within phosphatidylcholine (PC) in both the brain and blood of AD patients. Our previous work shows that pattern of DHA alterations seen in ε4 carriers with preclinical AD is similar to those seen in ε4 carriers with TBI or TBI +PTSD. While the brain is able to synthesize most lipids, DHA has to be acquired from the periphery since its de novo synthesis is insufficient to meet the high demand in the brain. Studies show that among ε4 carriers, transport of DHA to the brain is reduced compared to non-ε4 carriers, contributing to the pro-inflammatory and pro-amyloidogenic brain environment that is conducive to the development of AD. As such, increasing DHA transport into the brain could be important for preventing or treating AD among ε4 carriers who are at an exceptionally higher risk for developing AD and don't respond well to experimental AD treatments. Lyso-PC (LPC)-DHA is specially transported to the brain through a specialized transporter major facilitator superfamily domain containing 2A (mfsd2a) within the blood-brain-barrier (BBB). We have observed that the expression of mfds2a is reduced in the cerebrovasculature of ε4 carriers compared to non-ε4 carriers, in humans and in a mouse model of AD with human APOE4 gene (E4FAD). We observed that LPC-DHA levels are reduced in the brain parenchyma of ε4 AD patients compared to ε4 controls and non-ε4 AD patients and in E4FAD compared to E3FAD mice. We also observed an increase in matrix metalloproteinase 9 (MMP9) expression in ε4 AD patients and in E4FAD mice. We hypothesize that MMP9 activity is elevated in the presence of ε4 which leads to alterations of the cerebrovasculature, including reduced mfsd2a levels. This results in insufficient brain entry of LPC-DHA, inflammation, and exacerbated AD pathology. To address this problem, we will characterize DHA containing PC and LPC species within the brains of AD and control subjects stratified by different APOE genotypes and quantify corresponding changes in mfsd2a expression. Using EFAD mice, we will generate temporal profiles of PC and LPC-DHA changes and corresponding mfsd2a reduction and its relationship with AD pathology. Moreover, we will use both in vitro and in vivo approaches to determine whether the presence of the apoE4 isoform in the absence of mfsd2a leads to a reduction of LPC-DHA and free DHA transport into the brain and if boosting mfsd2a expression counteracts these effects. We will delve deeper into the fundamental role of MMP9 in the transport of lipids into the brain and evaluate the impact of MMP9-directed therapies on mfsd2a expression and LPC-DHA brain entry in AD. To this point, we have preliminary data indicating that increasing mfsd2a in the brain cerebrovasculature increases brain LPC-DHA levels and reduces inflammation in older E4FAD mice with well-established AD pathology. We find these observations to be extremely compelling as AD therapies have consistently failed in patients with 1) existing AD and 2) those carrying the ε4 allele. These preliminary findings shows promise in treating both of these notoriously resistant populations. Overall, these studies will elucidate mechanisms by which MMP9-mediated loss of mfsd2a causes reduced uptake of DHA in the brain and, additionally, will explore therapeutic avenues to increase LPC-DHA transport into the brain to prevent and treat AD, particularly in ε4 carriers.

超过20万美国退伍军人患有阿尔茨海默病（AD），预计这一数字还会增加