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.
|Zhao, Jing; Fu, Yuan; Liu, Chia-Chen et al. (2014) Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway. J Biol Chem 289:11282-92|
|Liu, Chia-Chen; Kanekiyo, Takahisa; Roth, Barbara et al. (2014) Tyrosine-based signal mediates LRP6 receptor endocytosis and desensitization of Wnt/?-catenin pathway signaling. J Biol Chem 289:27562-70|
|Divekar, Shailaja D; Burrell, Teal C; Lee, Jennifer E et al. (2014) Ligand-induced homotypic and heterotypic clustering of apolipoprotein E receptor 2. J Biol Chem 289:15894-903|
|Tamboli, Irfan Y; Heo, Dongeun; Rebeck, G William (2014) Extracellular proteolysis of apolipoprotein E (apoE) by secreted serine neuronal protease. PLoS One 9:e93120|
|Tai, Leon M; Koster, Kevin P; Luo, Jia et al. (2014) Amyloid-? pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. J Biol Chem 289:30538-55|
|Kunzler, Jacqueline; Youmans, Katherine L; Yu, Chunjiang et al. (2014) APOE modulates the effect of estrogen therapy on A* accumulation EFAD-Tg mice. Neurosci Lett 560:131-6|
|Gold, Brian T; Zhu, Zude; Brown, Christopher A et al. (2014) White matter integrity is associated with cerebrospinal fluid markers of Alzheimer's disease in normal adults. Neurobiol Aging 35:2263-71|
|Kanekiyo, Takahisa; Xu, Huaxi; Bu, Guojun (2014) ApoE and A? in Alzheimer's disease: accidental encounters or partners? Neuron 81:740-54|
|Rodriguez, Gustavo A; Tai, Leon M; LaDu, Mary Jo et al. (2014) Human APOE4 increases microglia reactivity at A? plaques in a mouse model of A? deposition. J Neuroinflammation 11:111|
|Nwabuisi-Heath, Evelyn; Rebeck, G William; Ladu, Mary Jo et al. (2014) ApoE4 delays dendritic spine formation during neuron development and accelerates loss of mature spines inýývitro. ASN Neuro 6:e00134|
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