Genetic association of an ( 2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease

Liao, Andrew; Nitsch, Roger M.; Greenberg, Steven M.; Finckh, Ulrich; Blacker, Deborah; Albert, Marilyn; Rebeck, G. William; Gómez-Isla, Teresa; Clatworthy, Anne E.; Binetti, Giuliano; Höck, Christoph; Mueller-Thomsen, Tomas; Mann, Ulrike; Zuchowski, Kathrin; Beisiegel, Ulrike; Staehelin, Hannes B.; Growdon, John H.; Tanzi, Rudolph E.; Hyman, Bradley T.

doi:10.1093/hmg/7.12.1953

Cited by 156 publications

(81 citation statements)

References 19 publications

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“…Several studies have demonstrated that LRP and its ligands, such as apolipoprotein E and ␣ 2 -macroglobulin, are associated with AD and alter A␤ metabolism (27)(28)(29)(30)(31)(32)(33)(34)(35). In this study, we demonstrated that a novel LDL receptor family member, LRP1B, which has high homology to LRP, can interact with APP and modulate its processing to A␤.…”

Section: Discussionmentioning

confidence: 61%

The Low Density Lipoprotein Receptor-related Protein 1B Retains β-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-β Peptide Production

Cam¹,

Zerbinatti²,

Knisely³

et al. 2004

Journal of Biological Chemistry

110

104

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The low density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a newly identified member of the LDL receptor family that shares high homology with the LDL receptor-related protein (LRP). LRP1B was originally described as a putative tumor suppressor in lung cancer cells; however, its expression profile in several regions of adult human brain suggests it may have additional functions in the central nervous system. Since LRP1B has overlapping ligand binding properties with LRP, we investigated whether LRP1B, like LRP, could interact with the ␤-amyloid precursor protein (APP) and modulate its processing to amyloid-␤ peptides (A␤s). Using an LRP1B minireceptor (mLRP1B4) generated to study the trafficking of LRP1B, we found that mLRP1B4 and APP form an immunoprecipitable complex. Furthermore mLRP1B4 bound and facilitated the degradation of a soluble isoform of APP containing a Kunitz proteinase inhibitor domain but not soluble APP lacking a Kunitz proteinase inhibitor domain. A functional consequence of mLRP1B4 expression was a significant accumulation of APP at the cell surface, which is likely related to the slow endocytosis rate of LRP1B. More importantly, mLRP1B4-expressing cells that accumulated cell surface APP produced less A␤ and secreted more soluble APP. These findings reveal that LRP1B is a novel binding partner of APP that functions to decrease APP processing to A␤. Consequently LRP1B expression could function to protect against the pathogenesis of Alzheimer's disease. Alzheimer's disease (AD)1 is characterized by the accumulation of neuritic plaques and neurofibrillary tangles in the brain.A major component of plaques is fibrillar aggregates of amyloid-␤ peptides (A␤s), which are derived from the processing of a ϳ120-kDa transmembrane protein known as ␤-amyloid precursor protein (APP) (1). APP, which exists in three main isoforms (APP695, APP751, and APP770), can undergo two post-translational processing pathways. In the amyloidogenic pathway, APP is cleaved first at a ␤-secretase site by the enzyme, ␤-site APP-cleaving enzyme, and subsequently by a ␥-secretase within its intramembrane region to release the A␤ peptide (2). In the non-amyloidogenic pathway, APP is processed by an ␣-secretase that clips within the A␤ region, resulting in the release of a soluble APP fragment (sAPP␣), which may function in blood coagulation and neurite outgrowth (3, 4). Several studies have shown that reducing APP endocytosis, either by biochemical methods or mutation of residues within its tail, results in a marked increase in sAPP␣ secretion and decrease in A␤ production, suggesting that these pathways are mutually exclusive (5, 6).In addition to modification by secretases, APP trafficking and processing are also regulated by other proteins, one of which is the low density lipoprotein (LDL) receptor-related protein (LRP). LRP is a multifunctional endocytic receptor that is highly expressed in the brain (7). LRP can internalize APP from the cell surface via extracellular interactions mediated by the Kunitz protein...

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Section: Discussionmentioning

confidence: 61%

The Low Density Lipoprotein Receptor-related Protein 1B Retains β-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-β Peptide Production

Cam¹,

Zerbinatti²,

Knisely³

et al. 2004

Journal of Biological Chemistry

110

104

View full text Add to dashboard Cite

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“…This exon is important because it encodes part of the bait region, where proteinases initiate reaction with ␣ 2 M by cleaving susceptible peptide bonds (15,16), and a segment of the growth factor binding sequence (17)(18)(19). In the second A2M gene polymorphism, Val-1000 is replaced by Ile (20). The linkage of A2M gene polymorphisms to late-onset AD remains incompletely understood, because the original observations have been confirmed in only a limited number of populations (21)(22)(23)(24)(25) and because there is no molecular explanation regarding how A2M gene mutations may affect ␣ 2 M structure, function, and expression.…”

mentioning

confidence: 99%

Distinct Binding Sites in the Structure of α2-Macroglobulin Mediate the Interaction with β-Amyloid Peptide and Growth Factors

Mettenburg

Webb

Gonias

2002

Journal of Biological Chemistry

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␣ 2 -Macroglobulin (␣ 2 M) and its receptor, low density lipoprotein receptor-related protein (LRP), function together to facilitate the cellular uptake and degradation of ␤-amyloid peptide (A␤). In this study, we demonstrate that A␤ binds selectively to ␣ 2 M that has been induced to undergo conformational change by reaction with methylamine. Denatured ␣ 2 M subunits, which were immobilized on polyvinylidene difluoride membranes, bound A␤, suggesting that ␣ 2 M tertiary and quaternary structure are not necessary. To determine whether a specific sequence in ␣ 2 M is responsible for A␤ binding, we prepared and analyzed defined ␣ 2 M fragments and glutathione S-transferase-␣ 2 M peptide fusion proteins. A single sequence, centered at amino acids (aa) 1314 -1365, was identified as the only major A␤-binding site. Impor Accumulation of ␤-amyloid peptide (A␤ and A␤ ) 1 in the brain plays a central role in the development and progression of Alzheimer's disease (AD) (1). Mutations in ␤-amyloid precursor protein (APP), which result in increased production of A␤, are associated with autosomal dominant forms of familial AD in humans (2-4). Mutated forms of human APP may also induce changes consistent with AD when expressed as transgenes in mice (5-8). Furthermore, immunization with A␤ (1-42) prevents progression of AD in animal model systems and may reverse symptoms by promoting resorption of A␤-containing plaques (9, 10). These results suggest that A␤ accumulation in the brain is a dynamic and reversible process. Proteins other than antibodies with the capacity to bind A␤ and promote its catabolism may influence disease progression.␣ 2 -Macroglobulin (␣ 2 M) is a 718-kDa homotetrameric glycoprotein, which is well characterized as an extracellular proteinase inhibitor (11) and as a carrier of specific growth factors, including transforming growth factor-␤ (TGF-␤) and nerve growth factor-␤ (NGF-␤) (12, 13). At least two separate polymorphisms in the A2M gene may be associated with increased risk of late-onset AD. The first involves a region within intron 17, at the 5Ј splice acceptor site for exon 18 (14). This exon is important because it encodes part of the bait region, where proteinases initiate reaction with ␣ 2 M by cleaving susceptible peptide bonds (15,16), and a segment of the growth factor binding sequence (17)(18)(19). In the second A2M gene polymorphism, Val-1000 is replaced by Ile (20). The linkage of A2M gene polymorphisms to late-onset AD remains incompletely understood, because the original observations have been confirmed in only a limited number of populations (21-25) and because there is no molecular explanation regarding how A2M gene mutations may affect ␣ 2 M structure, function, and expression.␣ 2 M is expressed by microglia, which accumulate near amyloid plaques (26). Thus, locally synthesized ␣ 2 M may affect AD progression by regulating the activity of various proteinases or by binding important growth factors. The previously demonstrated ability of ␣ 2 M to bind and neutralize the activity of TGF-...

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“…There seems that dimerization and LRP-1-ligand complex formation prevents the elimination of A 40 from the brain across the blood-brain barrier (Ito, et al 2007). There is also an over-representation of a common a2M polymorphism, Val1000 (GTC)/Ile1000 (ATC) in AD patients, which correlates with an increase in A burden (Kovacs 2000;Liao, et al 1998), further sustaining the importance of a2M in A clearance.…”

Section: Alpha2-macroglobulinmentioning

confidence: 99%

Key Enzymes and Proteins in Amyloid-Beta Production and Clearance

Santos¹,

Cardoso²,

Gonçalves³

2011

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets

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Genetic association of an ( 2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease

Cited by 156 publications

References 19 publications

The Low Density Lipoprotein Receptor-related Protein 1B Retains β-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-β Peptide Production

The Low Density Lipoprotein Receptor-related Protein 1B Retains β-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-β Peptide Production

Distinct Binding Sites in the Structure of α2-Macroglobulin Mediate the Interaction with β-Amyloid Peptide and Growth Factors

Key Enzymes and Proteins in Amyloid-Beta Production and Clearance

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