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Introduction Genetic abnormalities in the processing of amyloid precursor protein (APP) that induce an increase in amyloid-β (Aβ) peptide are causal factors, and the presence of the ε4 allele of apolipoprotein E (apoE) is the primary genetic risk factor for Alzheimer's disease (AD, Figure 1). The focus of our lab is understanding the role of Aβ and apoE in the brain.  Figure 1. Aβ is a 4kDa peptide proteolytically derived from the transmembrane protein APP (Figure 2). Aβ forms filaments that aggregate to form the amyloid plaques that are a pathological hallmark of AD. However, small, stable, oligomers of Aβ1-42 have been isolated from the brain, plasma, and cerebrospinal fluid (CSF), and in vitro data demonstrates that these soluble Aβ oligomers are neurotoxic and neuroinflammatory. Thus, the role of fibrillar and oligomeric assemblies of Aβ in the pathogenesis of AD is unclear (see also: Structure and Function of Aβ1-42 Assemblies).  Figure 2. In aqueous solutions, such as blood and interstitial fluid, hydrophobic lipids (fats) are packaged as lipoproteins. These particles contain proteins called apolipoproteins, which regulate lipid transport and clearance by acting as a ligand for cell surface lipoprotein receptors (Figure 3) ApoE is the primary apolipoprotein expressed in the brain. ApoE is a Protein of Lipoproteins  [Attribution: Unknown] Figure 3. In humans, apoE exists as three naturally occurring isoforms, ε2, ε3, and ε4 (Figure 4). ApoE4 is the primary risk factor for both familiar and sporadic forms of AD (Figure 5). Prior to this discovery, apoE was identified as a component of senile plaques and peripheral deposits of fibrillar Aβ. ApoE also associates with the soluble oligomers of Aβ found in the brain, plasma, and CSF. In vitro data confirms that apoE interacts with both fibrillar and soluble oligomers of Aβ. However, the effect, if any, of apoE isoform on these interactions has been difficult to determine, as the published results are contradictory. Types of Lipoproteins  [Attribution: Unknown] Figure 4. Apolipoprotein E  Figure 5. Thus, the link between apoE:Aβ interaction and AD remains unclear, as an apoE isoform-specific function has not been established that would explain the correlation between the ε4 allele and the disease. Our research focuses on understanding the effect of apoE isoforms on the structure and function of oligomeric and fibrillar Aβ aggregation assemblies.  Figure 6. Navigate through the following links for more detail: Apolipoprotein E and the Brain >> |
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