Megalin interacts with APP and the intracellular adapter protein FE65 in neurons

Alvira‐Botero, Ximena; Pérez‐González, Rocío; Spuch, Carlos; Vargas, Teodoro; Antequera, Desireé; Garzón, Miguel; Bermejo‐Pareja, Félix; Carro, Eva

doi:10.1016/j.mcn.2010.07.005

Cited by 58 publications

(35 citation statements)

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“…In this regard, interaction of APP with very low-density lipoprotein receptor (VLDLR) [223] and low-density lipoprotein receptor-related proteins (LRPs) [224, 225] , including megalin (also named LRP2) [226] , apolipoprotein E receptor 2 (ApoER2, also named LRP8) [227, 228] , or sortilin-related receptor containing LDLR class-A repeats (SORLA, also named LRP9) [229–232] are notable. It has been shown that the interaction of APP with LRP1 at the cell surface accelerates APP endocytosis, and enhances Aβ production [233] .…”

Section: Functional Consequence Of App Internalization On Aβ Clearancementioning

confidence: 99%

“…( b ) The schematics of several dimerization partners are shown. APP and its homologues can make homo- or heterodimers and form cell surface receptor-like complexes capable of modulating signaling events [56, 64, 151, 165, 167, 168, 170, 173, 175, 176, 226] . The extracellular region of APP-like receptor possesses the structural features to homodimerize or heterodimerize with its homologues in ( b1 ) cis- and ( b2 ) trans- cellular manner [65, 80, 151–153, 171, 172] .…”

Section: Figurementioning

confidence: 99%

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APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

112

110

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Amyloid Precursor Protein (APP) and its metabolites play a critical role in Alzheimer’s disease pathogenesis. The idea that APP may function as a receptor has gained momentum based on its structural similarities to type I transmembrane receptors, and the identification of putative APP ligands. Here we review the recent experimental evidence in support of this notion and discuss how this concept is viewed in the field. Specifically, we focus on the structural and functional characteristics of APP as a cell surface receptor, and its interaction with adaptors and signaling proteins. We also address the importance of APP's function as a receptor in Alzheimer’s disease etiology and discuss how this function might be potentially important for the development of novel therapeutic approaches.

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Section: Functional Consequence Of App Internalization On Aβ Clearancementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

112

110

View full text Add to dashboard Cite

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“…Its PTB1 domain mediates binding to the lipoprotein receptor-related protein (LRP) (isoform not specified) (15), the apolipoprotein E receptor APOER2 (LRP8) (16), and the very low-density lipoprotein receptor (17). This group of interacting proteins is completed by Megalin, another LRP family member (18), and the estrogen receptor alpha (19), for which the FE65 interacting domain is not yet known. Notably, the phosphorylation-dependent (20,21) LRP-FE65 binding affects the secretion of the secreted domain of APP ␣ and amyloid ␤ (8), and it is not hard to imagine that other FE65 interactions in this cellular compartment affect the cleavage of APP and putatively also of other transmembrane proteins mentioned above.…”

Section: Fe65 Is a Cytosolic Adapter Protein And An Important Bindingmentioning

confidence: 99%

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

Nensa

Neumann

Schrötter

et al. 2014

Molecular & Cellular Proteomics

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ller ‡ §ʈʈ FE65 is a cytosolic adapter protein and an important binding partner of amyloid precursor protein. Dependent on Thr668 phosphorylation in amyloid precursor protein, which influences amyloidogenic amyloid precursor protein processing, FE65 undergoes nuclear translocation, thereby transmitting a signal from the cell membrane to the nucleus. As this translocation may be relevant in Alzheimer disease, and as FE65 consists of three proteinprotein interaction domains able to bind and affect a variety of other proteins and downstream signaling pathways, the identification of the FE65 interactome is of central interest in Alzheimer disease research. In this study, we identified 121 proteins as new potential FE65 interacting proteins in a pulldown/mass spectrometry approach using human post-mortem brain samples as protein pools for recombinantly expressed FE65. Co-immunoprecipitation assays further validated the interaction of FE65 with the candidates SV2A and SERCA2. In parallel, we investigated the whole cell proteome of primary hippocampal neurons from FE65/FE65L1 double knockout mice. Notably, the validated FE65 binding proteins were also found to be differentially abundant in neurons derived from the FE65 knockout mice relative to wild-type control neurons. SERCA2 is an important player in cellular calcium homeostasis, which was found to be up-regulated in double knockout neurons. Indeed, knock-down of FE65 in HEK293T cells also evoked an elevated sensitivity to thapsigargin, a stressor specifically targeting the activity of SERCA2. Thus, our results suggest that FE65 is involved in the regulation of intracellular calcium homeostasis. Whereas transfection of FE65 alone caused a typical dotlike phenotype in the nucleus, co-transfection of SV2A significantly reduced the percentage of FE65 dot-positive cells, pointing to a possible role for SV2A in the modulation of FE65 intracellular targeting. Given that SV2A has a signaling function at the presynapse, its effect on FE65 intracellular localization suggests that the SV2A/FE65 interaction might play a role in synaptic signal transduction. Molecular

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“…Knockdown of megalin causes a significant increase in neurite branching in primary hippocampal neurons. 115) Megalin-null mice die perinatally due to insufficient respiration and developmental abnormalities in the lung. A deficiency of megalin causes severe abnormalities of the forebrain, a lack of the olfactory bulb in brain, and malformation of facial structures.…”

Section: Effects Of Apo E-containing Lipoproteins In Neurons and Gliamentioning

confidence: 99%

“…150) Megalin is a receptor for apo J, 112) and this receptor also interacts with amyloid precursor protein (APP) and its adaptor protein FE65 in hippocampal neurons. 115) Apo J can remove Ab from the CSF through the BBB to the peripheral circulation via megalin. 113) Thus, apo J seems to have a protective role in AD pathology and neurotoxicity.…”

Section: Lipid Metabolism and Admentioning

confidence: 99%

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFunctions of the central nervous system (CNS) are performed mainly by neurons and glia-primarily astrocytes, microglia and oligodendrocytes. It has been thought for a long time that glia only passively support neurons, but we now know that glia actively attend to assist in neuronal functions like synaptogenesis and neurotransmission. 1) Although it was believed that ca. 90% of the cells in the brain are glia and the rest of cells are neurons, Azevedo et al. recently reported that the numbers of neurons and non-neuronal cells (glia) are close to equal in human adult brain.2) Brain is the most cholesterol-rich organ in the body, and cholesterol metabolism in the CNS is tightly regulated between neurons and glia. [3][4][5][6][7] Imbalances in the metabolism of lipids, especially cholesterol, are closely linked to the development of several neurodegenerative disorders such as Alzheimer's disease, 8,9) Niemann-Pick type C disease 10) and Smith-Lemli Opitz syndrome. 11,12) In this review the regulation of lipid metabolism and the roles of glial lipoproteins in the CNS will be discussed. LIPID HOMEOSTASIS IN THE CNSThe system of lipid metabolism and transport in the CNS is different from that in peripheral tissues because the CNS is segregated from the peripheral circulation by the blood-brain barrier (BBB).13) Although lipoprotein particles can cross the BBB in vivo in Drosophila, which has a functional BBB like that in vertebrates, 14) lipoproteins in the mouse, rat and human do not cross the BBB. Consequently, since labeled cholesterol peripherally administrated was not found in the CNS of mammals, 15,16) cholesterol in the CNS is derived from de novo synthesis inside of the CNS. Furthermore, in the plasma of subjects who had liver transplantation the genotype of apolipoprotein (apo) E was that of the donor, whereas the subjects retained the own apo E genotype in the cerebrospinal fluid (CSF).17) Moreover, lipoproteins in the CNS consist of only high density lipoprotein (HDL)-like particles in contrast to the circulation which contains very low density lipoproteins (VLDL), low density lipoproteins (LDL) and HDL. It is known that the HDL-like particles in the CNS are secreted from glia (glial lipoproteins), mainly astrocytes and microglia, under normal conditions, [18][19][20] however lipoproteins can be secreted from neurons in vitro 21,22) and in vivo 23) under some specific conditions. Unesterified cholesterol is the major sterol in the adult brain, and small amounts of desmosterol and cholesteryl ester are also present. The majority (70-80%) of cholesterol in the adult brain is in myelin formed by oligodendrocytes. 24)Thus, the activity of cholesterol synthesis in the CNS is the highest during the myelinogenesis. After myelination, cholesterol synthesis continues at very low level in the CNS, and occurs mainly in astrocytes. 5,13,24) Neurons do not efficiently synthesize cholesterol and rely on external source of cholesterol from astrocytes, 25) so that neurons take up cholesterol as lipoproteins via ...

show abstract

Megalin interacts with APP and the intracellular adapter protein FE65 in neurons

Cited by 58 publications

References 50 publications

APP Receptor? To Be or Not To Be

APP Receptor? To Be or Not To Be

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

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