C‐terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65

Lakshmana, Madepalli K.; Chen, Eunice; Yoon, Il-Sang; Kang, David E.

doi:10.1111/j.1582-4934.2008.00320.x

Cited by 18 publications

(18 citation statements)

References 47 publications

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“…In transiently transfected HEK293T cells, RanBP9 markedly enhanced the levels of A␤ in the conditioned medium (supplemental Fig. S1), similar to that seen with the soluble LRP-C37 polypeptide (7). To confirm these results in a different cellular system, we stably transfected FLAG-RanBP9 in CHO cells stably expressing APP751 (CHO-APP751).…”

Section: Endogenous Ranbp9 Interacts With Lrp and App In Brain-mentioning

confidence: 74%

“…Although we had hypothesized that one or more NPXY domains in LRP-ST might underlie the pro-amyloidogenic processing of APP, we recently found that the 37 C-terminal residues of LRP (LRP-C37) lacking the NPXY motif was sufficient to robustly promote A␤ production independent of FE65 (7). Because LRP-C37 likely acts by recruiting other proteins, we used the LRP-C37 region as bait in a yeast two-hybrid screen, resulting in the identification of 4 new LRP-binding proteins (7). Among these, we focused on Ran-binding protein 9 (RanBP9) in this study, which we found to play a critical role in the trafficking and processing of APP.…”

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confidence: 99%

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Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Lakshmana

Yoon

Chen

et al. 2009

Journal of Biological Chemistry

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144

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Accumulation of the amyloid ␤ (A␤) peptide derived from the proteolytic processing of amyloid precursor protein (APP) is the defining pathological hallmark of Alzheimer disease. We previously demonstrated that the C-terminal 37 amino acids of lipoprotein receptor-related protein (LRP) robustly promoted A␤ generation independent of FE65 and specifically interacted with Ran-binding protein 9 (RanBP9). In this study we found that RanBP9 strongly increased BACE1 cleavage of APP and A␤ generation. This pro-amyloidogenic activity of RanBP9 did not depend on the KPI domain or the Swedish APP mutation. In cells expressing wild type APP, RanBP9 reduced cell surface APP and accelerated APP internalization, consistent with enhanced ␤-secretase processing in the endocytic pathway. The N-terminal half of RanBP9 containing SPRY-LisH domains not only interacted with LRP but also with APP and BACE1. Overexpression of RanBP9 resulted in the enhancement of APP interactions with LRP and BACE1 and increased lipid raft association of APP. Importantly, knockdown of endogenous RanBP9 significantly reduced A␤ generation in Chinese hamster ovary cells and in primary neurons, demonstrating its physiological role in BACE1 cleavage of APP. These findings not only implicate RanBP9 as a novel and potent regulator of APP processing but also as a potential therapeutic target for Alzheimer disease. The major defining pathological hallmark of Alzheimer disease (AD)2 is the accumulation of amyloid ␤ protein (A␤), a neurotoxic peptide derived from ␤-and ␥-secretase cleavages of the amyloid precursor protein (APP). The vast majority of APP is constitutively cleaved in the middle of the A␤ sequence by ␣-secretase (ADAM10/TACE/ADAM17) in the non-amyloidogenic pathway, thereby abrogating the generation of an intact A␤ peptide. Alternatively, a small proportion of APP is cleaved in the amyloidogenic pathway, leading to the secretion of A␤ peptides (37-42 amino acids) via two proteolytic enzymes, ␤-and ␥-secretase, known as BACE1 and presenilin, respectively (1).The proteolytic processing of APP to generate A␤ requires the trafficking of APP such that APP and BACE1 are brought together in close proximity for ␤-secretase cleavage to occur. We and others have shown that the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytosis receptor (2), binds to APP and alters its trafficking to promote A␤ generation. The loss of LRP substantially reduces A␤ release, a phenotype that is reversed when full-length (LRP-FL) or truncated LRP is transfected in LRP-deficient cells (3, 4). Specifically, LRP-CT lacking the extracellular ligand binding regions but containing the transmembrane domain and the cytoplasmic tail is capable of rescuing amyloidogenic processing of APP and A␤ release in LRP deficient cells (3). Moreover, the LRP soluble tail (LRP-ST) lacking the transmembrane domain and only containing the cytoplasmic tail of LRP is sufficient to enhance A␤ secretion (5). This activity of LRP-ST is achieved by promoting APP/BACE1 intera...

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Section: Endogenous Ranbp9 Interacts With Lrp and App In Brain-mentioning

confidence: 74%

mentioning

confidence: 99%

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Lakshmana

Yoon

Chen

et al. 2009

Journal of Biological Chemistry

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144

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“…The yeast two-hybrid screening was performed in the AH109 yeast strain, which contains three reporters (ADE2, HIS2, and MEL1). The bait plasmid was initially transformed into AH109, and growth was selected in SD dropout plates lacking tryptophan as described previously (15). These yeast strains expressing the RanBP9-LisH or RanBP9-SPRY domains were then used individually for mating with the Tyr-187 mating strain transformed with a cDNA library made from human brain and plated them on SD dropout plates lacking adenine, histidine, leucine, and tryptophan.…”

Section: Methodsmentioning

confidence: 99%

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

Wang

Dey

Carrera

et al. 2013

Journal of Biological Chemistry

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Background: Increased generation of toxic amyloid ␤ peptide (A␤) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Results: COPS5 (Jab1) is a novel RanBP9-interacting protein that robustly increases A␤ generation Conclusion: COPS5 increases A␤ generation by stabilizing RanBP9 protein levels. Significance: Lowering COPS5 levels may be an effective therapeutic approach for AD.

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“…Lakshmana and coworkers showed that LRP1 can promote amyloidogenic processing of APP also independent of Fe65, as only the last 37 C-terminal residues of LRP1 cytoplasmic tail, which do not contain the NPxY domains, possess this potential [110]. Furthermore, they identified four new proteins that can bind LRP1 irrespective of the NPxY domains [110].…”

Section: Peripheral Ab Clearance By Lrp1mentioning

confidence: 94%

Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease

Martiskainen

Haapasalo

Kurkinen

et al. 2013

Expert Opinion on Therapeutic Targets

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Due to the recent setbacks in the clinical trials targeting AD, it is instrumental to seek alternative therapeutic approaches, which aim to reduce the accumulation of Aβ in the brain tissue. As the ApoE/LRP1-mediated clearance of Aβ across the BBB is the key event in the regulation of Aβ transcytosis from brain to periphery, direct targeting of this protein entity at the BBB holds a great potential in the treatment of AD.

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C‐terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65

Cited by 18 publications

References 47 publications

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease

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