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Apolipoprotein E receptor pathways in Alzheimer disease

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Alzheimer disease (AD) is the most common neurodegenerative disease affecting millions of patients worldwide. According to the amyloid cascade hypothesis, the formation of neurotoxic oligomers composed of amyloid‐β (Aβ) peptides is the main mechanism that causes synaptic dysfunction and, eventually, neuronal cell death in this condition. Intriguingly, apolipoprotein E (apoE), the most important genetic risk factor for sporadic AD, emerges as a key factor that contributes to many aspects of the amyloid cascade including the clearance of Aβ from brain interstitial fluid and the ability of this peptide to form neurotoxic oligomers. Central to the activity of apoE in the healthy and in the diseased brain are apoE receptors that interact with this protein to mediate its multiple cellular and systemic effects. This review describes the molecular interactions that link apoE and its cellular receptors with neuronal viability and function, and how defects in these pathways in the brain promote neurodegeneration. This article is categorized under: Models of Systems Properties and Processes > Cellular Models Biological Mechanisms > Metabolism Physiology > Mammalian Physiology in Health and Disease

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Cellular brain cholesterol transfer pathways. In astrocytes, free cholesterol (FC) is associated with newly synthesized apolipoprotein E (apoE) (E) to form a lipoprotein particle that is released into the brain interstitial fluid (ISF). In addition, astrocytes also release FC via the ATP‐binding cassette transporter A1 (ABCA1) that associates with apoE‐containing lipoproteins in the extracellular fluid to further increase their lipid content. Conversion of FC to cholesterol ester (CE) by acyl‐coenzyme A acetyltransferase (ACAT) counteracts the lipidation of apoE. From the ISF, apoE‐containing lipoproteins are delivered to neurons via apoE receptors (E‐R) that bind the apolipoprotein and mediate endocytic uptake of the protein–lipid complex. In endosomes, E‐Rs discharge their ligand and return to the cell surface (not shown), whereas lipoproteins move to lysosomes where apoE and lipids are catabolized.
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The amyloid cascade hypothesis. (a) Amyloid precursor protein (APP) undergoes two alternative processing pathways. In the nonamyloidogenic pathway, APP is first cleaved within the amyloid‐β (Aβ) peptide sequence by a protease activity called α‐secretase (α) that produces soluble (s) APPα from the APP extracellular domain and a membrane‐anchored fragment CTFα. Subsequently, γ‐secretase activity (γ) cleaves CTFα into peptide P3 and the soluble APP intracellular domain (AICD). The amyloidogenic pathway is initiated by the cleavage of APP by β‐secretase (β‐site APP‐cleaving enzyme‐1, BACE1) at the amino‐terminal end of the Aβ sequence followed by γ‐secretase cleavage at its carboxyl terminus. These steps produce Aβ peptides of 37‐ to 43‐amino acid length, as well as sAPPβ and the AICD. (b) APP processing produces monomeric Aβ molecules that are released into the extracellular space where they aggregate into neurotoxic oligomers. According to the amyloid cascade hypothesis, the concentration of toxic Aβ species in the brain is the crucial factor for induction of neuronal cell death. Levels of toxic Aβ oligomers are influenced by the kinetics of APP processing and Aβ aggregation, and by the rate of clearance of monomeric Aβ molecules.
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ApoE4 causes removal of apolipoprotein E (apoE) receptors from the neuronal cell surface and promotes synaptic dysfunction. Amyloid‐β (Aβ) induces the internalization of NMDA receptors (NMDARs) from the postsynaptic membrane, resulting in suppression of synaptic activity (step 1). Binding of reelin to the apoE receptor 2 (ApoER2) results in an intracellular signal cascade that prevents Aβ‐induced internalization of NMDAR (step 2). The protective function of the reelin–ApoER2 pathway is inhibited by binding of apoE4 to ApoER2, resulting in intracellular accumulation of apoE4/ApoER2 complexes and depletion of ApoER2 molecules from the postsynaptic membranes (step 3).
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Pathways for cellular clearance and blood–brain barrier (BBB) export of free or apolipoprotein E (apoE)‐bound amyloid‐β (Aβ). (a) In the brain interstitial fluid (ISF), cellular uptake and lysosomal catabolism of soluble Aβ is mediated by low‐density lipoprotein (LDL) receptors (LDLRs) in astrocytes and microglia, and by LRP1 in neurons. Alternatively, soluble Aβ is transported across the BBB by LRP1. In the circulation Aβ associates with a soluble fragment of LRP1 (sLRP1) preventing transfer of the peptide back into the ISF via transporters such as the receptor for advanced glycation end products (RAGE). (b) In the ISF, free Aβ may also associate with apoE (E). Complex formation reduces the extent of BBB export but promotes cellular catabolism in the brain parenchyma by apoE receptors on neurons (LRP1, sortilin) and astrocytes (LDL receptor).
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The apolipoprotein E (apoE) receptor SORLA (sorting protein‐related receptor with A‐type repeats) determines monomeric versus dimeric processing of APP by BACE1. In the preferred mode of action, BACE1 monomers form homodimers that act on APP homodimers to produce CTFβs (dimer processing). The association of SORLA with APP monomers prevents APP dimer formation, requiring BACE1 monomers to act on the nonpreferred monomeric APP substrate (monomer processing). Association of BACE1 with APP is fostered by the membrane cholesterol content (C) promoting sequestration of enzyme and substrate in lipid rafts.
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Pathways of intracellular APP transport. (a) Newly synthesized APP molecules traverse the trans‐Golgi compartment (TGN) to the plasma membrane where most precursor molecules are cleaved by α‐secretase producing sAPPα. Nonprocessed precursors internalize from the cell surface via clathrin‐mediated endocytosis. From early endosomes, APP moves to endosomal compartments for amyloidogenic processing through sequential cleavage by β‐ and γ‐secretases generating sAPPβ and amyloid‐β (Aβ). (b) Trafficking of APP in neurons is controlled by apoE receptors. At the cell surface, association of APP with LRP1 (step 1) stimulates endocytic uptake and intracellular processing of APP to Aβ in endosomes (step 2). In contrast, interaction with the slow‐endocytosing receptor apolipoprotein E receptor 2 (ApoER2) delays endocytosis of APP (step 3). Binding of APP to SORLA in endosomes results in retrograde sorting of APP to the TGN (step 4), counteracting amyloidogenic processing in the endocytic compartment. LRP1B acts similar to ApoER2 in delaying endocytosis of APP (not shown).
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