BRAIN LIPID METABOLISM, DENDRITES AND SYNAPSES IN AGING AND ALZHEIMER'S DISEASE

衰老和阿尔茨海默病中的脑脂质代谢、树突和突触

• 批准号: 8516928
• 负责人: GUOJUN BU
• 金额: $ 28.86万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516928
• 关键词: Age; Age-Months; Aging; Alleles; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Biogenesis; Brain; Breeding; Cerebrosides; Cholesterol; Cholesterol Homeostasis; Coculture Techniques; Complement; Defect; Dendrites; Dendritic Spines; Dependovirus; Down-Regulation; Exhibits; Family; Glial Fibrillary Acidic Protein; Goals; Health; Homeostasis; Human; Impairment; Inferior; Knockout Mice; Knowledge; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Measures; Mediating; Membrane; Memory impairment; Metabolic Pathway; Metabolism; Methods; Molecular; Movement Disorders; Mus; Neurites; Neuroglia; Neurons; Pathogenesis; Pathology; Pathway interactions; Peptides; Play; Process; Production; Prosencephalon; Protein Isoforms; Proteins; Public Health; Reagent; Risk; Risk Factors; Role; Signal Transduction; Staging; Synapses; System; Testing; Transgenic Mice; Vertebral column; abstracting; age related; aging brain; apolipoprotein E-3; apolipoprotein E-4; base; cholesterol sulfatide; density; lipid metabolism; lipid transport; nervous system disorder; novel; novel strategies; overexpression; particle; receptor; receptor expression; receptor function; small hairpin RNA; synaptic function; synaptogenesis

PROJECT SUMMARY/ABSTRACT Brain lipids such as cholesterol play critical roles in neuronal membrane homeostasis and synapse functions. However, the mechanisms that govern their biogenesis and transport to neurons are poorly understood. Apolipoprotein E (apoE) is a major lipid transporter in the brain. Of the three human apoE isoforms (E2, E3 and E4), apoE4 is the predominant risk allele for late-onset AD. Brain apoE/lipoprotein particles, produced primarily by astrocytes, deliver cholesterol and other lipids to neurons via apoE receptors, which belong to the low-density lipoprotein receptor (LDLR) family. To ultimately understand why apoE4 is a risk factor for AD, it is essential to study the differential functions of apoE isoforms in brain lipid transport and synapse functions, and what specific roles apoE receptors play in these processes. We have demonstrated that brain apoE metabolism is mediated by both LDLR and LDLR-related protein 1 (LRP1). However, neuronal deletion of Lrp1, but not Ldlr, impairs cholesterol metabolism in mice. This suggests that LRP1 is the predominant cholesterol transport receptor in neurons. Conditional Lrp1 forebrain knockout (LRP1-KO) mice have decreased brain cholesterol, sulfatide and cerebroside; reduced dendritic spine density and branching; fewer synapses; and diminished synaptic functions. LRP1-KO mice have memory deficits and movement disorders consistent with compromised dendritic spine/synaptic integrity and synaptic functions. Interestingly, LRP1 levels are significantly reduced in human AD brains and in the apoE4-targeted replacement (TR) mice. ApoE4-TR, but not apoE3-TR mice, also exhibit impaired lipid metabolism and synaptic functions, and apoE4 is less stable compared to apoE3. Based on these observations, we hypothesize that apoE4 is inferior to apoE3 in transporting brain lipid and in supporting dendritic spine/synaptic integrity, particularly in aging brains, and that these apoE4 defects can be partially rescued by restoring the expression and function of apoE receptor LRP1. We propose three aims to test our hypothesis. In Aim 1, we will dissect the molecular and cellular mechanisms by which apoE isoforms transport lipids and regulate neuronal functions via LRP1- and LDLR-dependent pathways using astrocytes-secreted apoE/lipoprotein particles and glia-neuron co-culture system. In Aim 2, we will define age-dependent effects of apoE4 on brain lipid metabolism and synaptic functions and examine whether aging brains are more sensitive to the inferior functions of apoE4. In Aim 3, we will determine if overexpressed LRP1 in mouse brains is sufficient to rescue lipid and synaptic impairments in apoE4-TR mice by breeding apoE3-TR and apoE4-TR mice with LRP1 transgenic mice. Together, our proposed studies should generate critical knowledge on how apoE isoforms differentially regulate brain lipid metabolism and synaptic functions via apoE receptors, and why apoE4 is a strong risk factor for AD. Our studies may also define apoE and apoE receptors as critical targets for AD therapy.

PROJECT SUMMARY/ABSTRACT Brain lipids such as cholesterol play critical roles in neuronal membrane homeostasis and synapse functions. However, the mechanisms that govern their biogenesis and transport to neurons are poorly understood. Apolipoprotein E (apoE) is a major lipid transporter in the brain. Of the three human apoE isoforms (E2, E3 and E4), apoE4 is the predominant risk allele for late-onset AD. Brain apoE/lipoprotein particles, produced primarily by astrocytes, deliver cholesterol and other lipids to neurons via apoE receptors, which belong to the low-density lipoprotein receptor (LDLR) family. To ultimately understand why apoE4 is a risk factor for AD, it is essential to study the differential functions of apoE isoforms in brain lipid transport and synapse functions, and what specific roles apoE receptors play in these processes. We have demonstrated that brain apoE metabolism is mediated by both LDLR and LDLR-related protein 1 (LRP1). However, neuronal deletion of Lrp1, but not Ldlr, impairs cholesterol metabolism in mice. This suggests that LRP1 is the predominant cholesterol transport receptor in neurons. Conditional Lrp1 forebrain knockout (LRP1-KO) mice have decreased brain cholesterol, sulfatide and cerebroside; reduced dendritic spine density and branching; fewer synapses; and diminished synaptic functions. LRP1-KO mice have memory deficits and movement disorders consistent with compromised dendritic spine/synaptic integrity and synaptic functions. Interestingly, LRP1 levels are significantly reduced in human AD brains and in the apoE4-targeted replacement (TR) mice. ApoE4-TR, but not apoE3-TR mice, also exhibit impaired lipid metabolism and synaptic functions, and apoE4 is less stable compared to apoE3. Based on these observations, we hypothesize that apoE4 is inferior to apoE3 in transporting brain lipid and in supporting dendritic spine/synaptic integrity, particularly in aging brains, and that these apoE4 defects can be partially rescued by restoring the expression and function of apoE receptor LRP1. We propose three aims to test our hypothesis. In Aim 1, we will dissect the molecular and cellular mechanisms by which apoE isoforms transport lipids and regulate neuronal functions via LRP1- and LDLR-dependent pathways using astrocytes-secreted apoE/lipoprotein particles and glia-neuron co-culture system. In Aim 2, we will define age-dependent effects of apoE4 on brain lipid metabolism and synaptic functions and examine whether aging brains are more sensitive to the inferior functions of apoE4. In Aim 3, we will determine if overexpressed LRP1 in mouse brains is sufficient to rescue lipid and synaptic impairments in apoE4-TR mice by breeding apoE3-TR and apoE4-TR mice with LRP1 transgenic mice. Together, our proposed studies should generate critical knowledge on how apoE isoforms differentially regulate brain lipid metabolism and synaptic functions via apoE receptors, and why apoE4 is a strong risk factor for AD. Our studies may also define apoE and apoE receptors as critical targets for AD therapy.