Among a number of critical questions that remain unanswered about the role of apoE and apoE receptors in neurons is whether the apoE receptor-mediated metabolism of apoE by neurons is isoform-specific. The only way to address this question is to generate the forms of apoE-lipoproteins found in the CMS and examine their interactions with each apoE receptor expressed in the brain. We propose that apoE isoforms and AB42 affect the apoE receptor-mediated metabolism of apoE by neurons. We will address this hypothesis in the following Specific Aims, elucidating the effects of the following variables on several key components of apoE metabolism: (i) the unique properties of glial-apoE isoforms, as compared to other common sources of apoE, (ii) neuron-specific apoE receptors, and (iii) oligomeric and fibrillar Ap42.
Specific Aim 1 : Evaluate the effects of apoE source, apoE isoform and A|342 on the binding of apoE to brain apoE receptors.
Specific Aim 2 : Examine the effects of apoE isoform, apoE receptor and Ap42 on metabolism and recycling of apoE by neurons in vitro.
Specific Aim 3 : Determine the effects of apoE isoform, apoE receptor, and Ap42 on intraneuronal trafficking of apoE, intraneuronal Ap accumulation and neuronal viability in vitro. Our specific hypotheses are that apoE source, apoE isoform and Ap42 influence apoE binding to apoE receptors expressed by neurons (Aim 1), that apoE receptor-mediated metabolism, specifically recycling, of apoE4 in neurons is impaired compared to apoE2 or E3 (Aim 2), and that altered trafficking of apoE4 facilitates intraneuronal Ap42 accumulation, compromising neuronal viability (Aim 3). These predictions provide a potential cellular basis for our key observation that apoE4 and oligomeric Ap42 act together to reduce neuronal viability, an effect that requires apoE receptors. Defining the effects of human apoE isoforms and Ap42 on apoE receptor-mediated metabolism of apoE by neurons, intraneuronal Ap accumulation and neuronal viability is essential to identifying apoE isoform-specific functions that ultimately effect the neuronal loss associated with AD. This proposal may also facilitate the development of a cellbased screening assay to identify a unique AD therapeutic based on modulating these pathways.
|Brown, Christopher A; Jiang, Yang; Smith, Charles D et al. (2018) Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities. Cortex 104:58-74|
|Gold, Brian T; Brown, Christopher A; Hakun, Jonathan G et al. (2017) Clinically silent Alzheimer's and vascular pathologies influence brain networks supporting executive function in healthy older adults. Neurobiol Aging 58:102-111|
|Brown, Christopher A; Johnson, Nathan F; Anderson-Mooney, Amelia J et al. (2017) Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease. Neuroimage Clin 13:106-115|
|Di Battista, Amanda M; Heinsinger, Nicolette M; Rebeck, G William (2016) Alzheimer's Disease Genetic Risk Factor APOE-?4 Also Affects Normal Brain Function. Curr Alzheimer Res 13:1200-1207|
|Yang, Longyu; Liu, Chia-Chen; Zheng, Honghua et al. (2016) LRP1 modulates the microglial immune response via regulation of JNK and NF-?B signaling pathways. J Neuroinflammation 13:304|
|DiBattista, Amanda M; Dumanis, Sonya B; Newman, Joshua et al. (2016) Identification and modification of amyloid-independent phenotypes of APOE4 mice. Exp Neurol 280:97-105|
|Fu, Yuan; Zhao, Jing; Atagi, Yuka et al. (2016) Apolipoprotein E lipoprotein particles inhibit amyloid-? uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener 11:37|
|Teter, Bruce; LaDu, Mary Jo; Sullivan, Patrick M et al. (2016) Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain. Neuroreport 27:791-5|
|Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra et al. (2016) The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice. Neurobiol Aging 37:47-57|
|Ghura, Shivesh; Tai, Leon; Zhao, Ming et al. (2016) Arabidopsis thaliana extracts optimized for polyphenols production as potential therapeutics for the APOE-modulated neuroinflammation characteristic of Alzheimer's disease in vitro. Sci Rep 6:29364|
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