Brain lipids such as cholesterol play critical roles in neuronal membrane homeostasis and synapsefunctions. However, the mechanisms that govern their biogenesis and transport to neurons are poorlyunderstood. 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, whichbelong to the low-density lipoprotein receptor (LDLR) family. To ultimately understand why apoE4 is a riskfactor for AD, it is essential to study the differential functions of apoE isoforms in brain lipid transport andsynapse functions, and what specific roles apoE receptors play in these processes. We have demonstratedthat brain apoE metabolism is mediated by both LDLR and LDLR-related protein 1 (LRP1). However, neuronaldeletion of Lrp1, but not Ldlr, impairs cholesterol metabolism in mice. This suggests that LRP1 is thepredominant cholesterol transport receptor in neurons. Conditional Lrp1 forebrain knockout (LRP1-KO) micehave 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 movementdisorders 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 apoE4is less stable compared to apoE3. Based on these observations, we hypothesize that apoE4 is inferior toapoE3 in transporting brain lipid and in supporting dendritic spine/synaptic integrity, particularly inaging brains, and that these apoE4 defects can be partially rescued by restoring the expression andfunction of apoE receptor LRP1. We propose three aims to test our hypothesis.
In Aim 1, we will dissect themolecular and cellular mechanisms by which apoE isoforms transport lipids and regulate neuronal functions viaLRP1- and LDLR-dependent pathways using astrocytes-secreted apoE/lipoprotein particles and glia-neuronco-culture system.
In Aim 2, we will define age-dependent effects of apoE4 on brain lipid metabolism andsynaptic 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 synapticimpairments 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 differentiallyregulate brain lipid metabolism and synaptic functions via apoE receptors, and why apoE4 is a strong riskfactor for AD. Our studies may also define apoE and apoE receptors as critical targets for AD therapy.

Public Health Relevance

Understanding the mechanisms by which apoE isoforms and apoE receptors differentially regulate brain lipid metabolism and synaptic functions is important for developing novel treatments for AD, an ominous public health menace. If our hypothesis is proven, pharmacological reagents can be developed to enhance the function of apoE4 in brain lipid transport, and to restore the expression of apoE receptor LRP1 in AD. These novel strategies should complement treatment methods targeting amyloid-beta peptide production and aggregation in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG035355-03
Application #
8206522
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Petanceska, Suzana
Project Start
2010-12-15
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$305,421
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
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