Apolipoprotein (apo) E4 has been identified as a major risk factor or susceptibility gene for the development of Alzheimer's disease and other neurodegenerative disorders. Several hypotheses have been advanced to explain this association, including its role in altering amyloid beta (Abeta) peptide clearance and/or deposition (plaque formation), altering tau phosphorylation and microtubule biology (tangle formation), and altering cytoskeletal structure and function (remodeling and repair). Thus, apoE3 and apoE4 may impact neurobiology and neuropathology through multiple processes or pathways. In fact, it is reasonable to speculate that under various physiological or pathological conditions apoE may play different roles, some of which undoubtedly remain to be elucidated. Recent preliminary studies have extended our understanding of isoform-specific effects of apoE on neurons and may shed light on additional unique roles for apoE in neurobiology. First, apoE4 stimulates Abeta production in neuronal cells to a greater extent than apoE3 and the enhanced Abeta production is associated with increased amyloid precursor protein recycling. Sccond, apoE4 potentiates Abeta-induced lysosomal leakage and cell death whereas apoE3 does not. Third, apoE4 undergoes proteolytic cleavage to form intracellular carboxyl-terminal-truncated forms of apoE that induce neurofibrillary tangle-like inclusion formation in neurons (apoE4 > apoE3). Transgenic apoE4 mice expressing apoE in neurons have increased levels of tangle-like structures and phosphorylated tau inclusion bodies in neurons. The goal of this project is to investigate the mechanisms whereby apoE3 versus apoE4 alters these cellular pathways, including the apoE isoform-specific effects on Abeta production (Aim 1), Abeta-induced lysosomal leakage (Aim 2), and the formation of neurofibrillary tangle-like inclusions in neurons associated with the generation of bioactive intracellular proteolytic fragments of apoE (Aim 3). We will determine how these cellular pathways are modulated by the unique structural (conformational) characteristics of apoE, including domain interaction, in which the amino- and carboxyl-terminal domains interact only in apoE4 (arginine-61 reacting with glutamic acid-255) and molecular instability, in which apoE4 more readily forms reactive folding intermediates than apoE3. These studies, involving both in vitro and in vivo approaches, will provide additional insights into the role of apoE4 and may identify new therapeutic targets for apoE4-associated neuropathological disorders.

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Overk, Cassia; Masliah, Eliezer (2017) Perspective on the calcium dyshomeostasis hypothesis in the pathogenesis of selective neuronal degeneration in animal models of Alzheimer's disease. Alzheimers Dement 13:183-185
Valera, Elvira; Spencer, Brian; Mott, Jennifer et al. (2017) MicroRNA-101 Modulates Autophagy and Oligodendroglial Alpha-Synuclein Accumulation in Multiple System Atrophy. Front Mol Neurosci 10:329
Valera, Elvira; Spencer, Brian; Fields, Jerel A et al. (2017) Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun 5:2
Spencer, Brian; Desplats, Paula A; Overk, Cassia R et al. (2016) Reducing Endogenous ?-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci 36:7971-84
Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) ?-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352
Spencer, Brian; Potkar, Rewati; Metcalf, Jeff et al. (2016) Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease. J Biol Chem 291:1905-20
Valera, E; Monzio Compagnoni, G; Masliah, E (2016) Review: Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy. Neuropathol Appl Neurobiol 42:95-106
Valera, Elvira; Spencer, Brian; Masliah, Eliezer (2016) Immunotherapeutic Approaches Targeting Amyloid-?, ?-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13:179-89
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34

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