Interaction of Apolipoprotein J-Amyloid β-Peptide Complex with Low Density Lipoprotein Receptor-related Protein-2/Megalin

Hammad, Samar M.; Ranganathan, Sripriya; Loukinova, Elena; Twal, Waleed O.; Argraves, W. Scott

doi:10.1074/jbc.272.30.18644

Cited by 184 publications

(143 citation statements)

References 35 publications

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“…A specific transport system for sA/31~o has been demonstrated in an in vitro mode! of human BBB (Z!okovic et a!., 1997), and megalin-mediated transport of sA/31~o-apoJ complex has been shown at the BBB (Z!okovic et a!., 1996) and in other tissues (Hammad et al, 1997). Several molecules, such as the receptor for advanced glycation end products (Yan et al, 1996), scavenger receptor, and low-and high-density lipoprotein receptors, have been identified as possible candidates for receptor-mediated endothelia!…”

Section: Discussionmentioning

confidence: 99%

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

Mačkić¹,

Weiss²,

Miao³

et al. 1998

Journal of Neurochemistry

132

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Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and bloodbrain barrier (BBB) permeability to 1251-amyloid~3(1 -40) synthetic peptide (sA/3 1_40) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sA/31_40, t~12, was prolonged by 0.6 h, the systemic clearance,~was reduced from 1.8 to 1.1 mI/mm/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sA/31_40 was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sA/3140 by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, and 2.1 -fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sA/31_40 remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sA/3140, and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sAft~40, and reduced brain metabolism to enhance the development of CAA. Key Words: Alzheimer's amyloid /3-Cerebrovascular amybid angiopathy-Squirrel monkey-Cerebrovascular sequestration-Blood-brain barrier permeability-Aging.

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Section: Discussionmentioning

confidence: 99%

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

Mačkić¹,

Weiss²,

Miao³

et al. 1998

Journal of Neurochemistry

132

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“…Clusterin has long been known to interact with the cell surface receptor megalin (LRP2) and to complex with Aβ to mediate its uptake by megalin and subsequent degradation (Hammad et al, 1997). It also interacts with other members of the low density lipoprotein (LDL) receptor family -it binds to chicken LR8 and an LDLR-related protein (Mahon et al, 1999), and uptake of clusterin-leptin complexes by apoER2 and VLDLR has been proposed to facilitate leptin clearance (Bajari et al, 2003).…”

Section: Clusterinmentioning

confidence: 99%

“…(3) It has previously been shown that clusterin-Aβ complexes bind to megalin on the surface of mouse teratocarcinoma F9 cells, and are subsequently internalised, transported to lysosomes and degraded (Hammad et al, 1997). Similarly, α2M-Aβ complexes are internalized via LRP expressed on U87 cells and are subsequently degraded (Narita et al, 1997).…”

Section: Ecs and Protein Disposal In The Brainmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…Rabbit polydonal antiserum to porcine megalin has also been described (Hammad et al, 1997). phenylmethylsulfonyl fluoride (PMSF), 10llg/mlleupeptin, lOIlg/ml aprotinin, pH 7.6) using a Tekmar tissumizer at half speed for l min.…”

Section: Methodsmentioning

confidence: 99%

Co‐expression and interaction of cubilin and megalin in the adult male rat reproductive system

Praet

Argraves

Morales

2002

Molecular Reproduction Devel

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Cubilin is a peripheral membrane protein that cooperates with the endocytic receptor megalin to mediate endocytosis of ligands in various polarized epithelia. Megalin is expressed in the male reproductive tract where it has been implicated in the process of sperm membrane remodeling. A potential role for cubilin in the male reproductive tract has not been explored. Using RT‐PCR, we found that cubilin and megalin mRNAs are expressed in the efferent ducts, corpus and cauda epididymis, and proximal and distal vas deferens. Immunohistological analysis revealed that cubilin was expressed in nonciliated cells of the efferent ducts, principal cells of the corpus and cauda epididymis and vas deferens. Immunogold EM showed cubilin in endocytic pits, endocytic vesicles, and endosomes of these cells. The expression profile of cubilin in the male reproductive tract was coincident with that of megalin except in principal cells of the caput epididymis. Double immunogold labeling showed that cubilin and megalin co‐localized within the endocytic apparatus and recycling vesicles of efferent duct cells. Neither protein was found in lysosomes. Injection of RAP, an antagonist of megalin interaction with cubilin, reduced the level of intracellular cubilin in cells of the efferent ducts and vas deferens. In conclusion, cubilin and megalin are co‐expressed in cells of the epididymis and vas deferens and the endocytosis of cubilin in these tissues is dependent on megalin. Together, these findings highlight the potential for a joint endocytic role for cubilin and megalin in the male reproductive tract. Mol. Reprod. Dev. 64: 129–135, 2003. © 2003 Wiley‐Liss, Inc.

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Interaction of Apolipoprotein J-Amyloid β-Peptide Complex with Low Density Lipoprotein Receptor-related Protein-2/Megalin

Cited by 184 publications

References 35 publications

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

Extracellular Chaperones and Amyloids

Co‐expression and interaction of cubilin and megalin in the adult male rat reproductive system

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