Low-density Lipoprotein Receptor Related Protein (LRP) and Apolipoprotein E-mediated Regulation of Amyloid Precursor Protein (APP) Expression and Processing in the Rat Dentate Gyrus During Memory Consolidation PDF Download
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Author: Lisa A. M. Conboy
Publisher:
ISBN:
Category : Alzheimer's disease
Languages : en
Pages : 197
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Book Description
Author: Lisa A. M. Conboy
Publisher:
ISBN:
Category : Alzheimer's disease
Languages : en
Pages : 197
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Book Description
Author: Emily Van Uden
Publisher:
ISBN:
Category :
Languages : en
Pages : 272
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Author: David Eun-Kwang Kang
Publisher:
ISBN:
Category :
Languages : en
Pages : 390
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Book Description
![The Mechanism of the Low-density Lipoprotein Receptor-related Protein (LRP) in the Production of Amyloid-[Beta] Peptide PDF](https://books.google.com/books/content/images/frontcover/MhqhDAEACAAJ?fife=w80-h100)
Author: Eunice Chungyu Chen
Publisher:
ISBN:
Category :
Languages : en
Pages : 46
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Book Description
Alzheimer's disease (AD) is the most common form of neurodegenerative disorder affecting the elderly, presenting symptoms such as memory impairment and dementia. AD is pathologically characterized by the development of extracellular senile plaques and intracellular neurofibrillary tangles (NFT). The plaques are composed of amyloid-[Beta] peptide (A[Beta]) and the NFTs are composed of a hyperphosphorylated form of the tau protein. A[Beta] is formed by sequential proteolytic processing of the amyloid precursor protein (APP) by [Beta]-, and [Gamma]-secretase. Accordingly, alterations in APP processing result in increased A[Beta] generation. The low-density lipoprotein receptor-related protein (LRP) is a large endocytic protein involved in diverse biological functions. It has been hypothesized that LRP plays a dual role in AD, playing a role in both the clearance and the production of A[Beta]. Previous studies have shown that the cytoplasmic tail alone is able to promote A[Beta] generation and promote APP processing. This study seeks to determine the area of the cytoplasmic tail responsible for pro-amyloidogenic activity and how it occurs. Our findings indicate that the last 37 amino acids of the tail, containing a dileucine motif, are sufficient. Additionally, LRP facilitates the generation of A[Beta] by trafficking APP and BACE1 to the lipid raft domains. This function of LRP may be altered due to the presence of a Kunitz protease inhibitor (KPI) domain on APP. The results of our study have therapeutic potential to reduce [Beta]-amyloid by understanding the function of LRP in the amyloidogenic processing of APP.
Author: Miklos Guttman
Publisher:
ISBN:
Category :
Languages : en
Pages : 184
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Book Description
The LDLR family of receptors mediates the uptake of lipoprotein particles, and is essential for cholesterol homeostasis. The LDL receptor-related protein 1 (LRP-1) mediates internalization of a large number of diverse ligands and is widely implicated in Alzheimer's disease. Clusters of complement-type ligand binding repeats (CRs) in the LDL receptor family are thought to mediate the interactions between these receptors and their various ligands. Apolipoprotein E, a key ligand for cholesterol homeostasis, has been shown to interact with LDLR, LRP and VLDLR, through these clusters. LDLR and VLDLR each contain a single ligand-binding repeat cluster, whereas LRP contains three large clusters of ligand binding repeats, each with ligand binding functions. In order to study smaller units of these ligand binding clusters we have engineered a new approach to express and refold complement repeat (CR) domains in E. coli. This successfully produced high yields of refolded protein with the benefit of inexpensive isotope labeling for NMR studies. We have expressed a subdomain of sLRP3 (CR16-18) that has previously been shown to recapitulate ligand binding to the isolated receptor binding portion of ApoE (residues 130-149). Binding experiments with the ApoE recognition region of LDLR (LA3-5) and CR16-18 showed that each CR could interact with ApoE(130-149) and that a conserved W25/D30 pair within each repeat appears critical for high affinity. The triple repeat LA3-5 showed the expected interaction with the lipid complexed ApoE(1-191)*DMPC, but surprisingly CR16-18 did not interact with this form of ApoE. To understand these differences in ApoE binding affinity, we introduced mutations of conserved residues from LA5 into CR18, and produced a CR16-18 variant capable of binding ApoE(1-191)*DMPC. This change cannot fully be accounted for by the interaction with ApoE's proposed receptor binding region, therefore we speculate that LA5 is recognizing a distinct epitope on ApoE that may only exist in the lipid bound form. The combination of avidity effects with this distinct recognition process likely governs the ApoE-LDL receptor interaction. Since even the strongest interaction between ApoE(130-149) and a single repeat (CR17) was relatively weak, we constructed a CR17-ApoE(130-149) fusion protein to stabilize the interface for structural studies. The structure revealed a motif seen previously in all ligand CR interactions, in which lysine residues of the ligand interact with the calcium binding site of the CR. Like many ligands of CRs ApoE(130-149) binds as a helix, but with an unexpected turn at H140. These studies also revealed that little structural rearrangement occurs within CR17 upon binding. In addition, dynamics measurements of the free and bound CR17 reveal that certain regions become more ordered, while others become less ordered upon binding. The cytoplasmic tail of LRP, containing two NPXY motifs, has been implicated in the onset of Alzheimer's disease. To examine the intracellular interactions of LRP, as well as to separate which proteins bind to each NPXY motif and their phosphorylation dependence, each NPXY motif microdomain was prepared in both phosphorylated and non-phosphorylated forms and used to probe rodent brain extracts for binding proteins. Proteins that bound specifically to the microdomains were identified by LC-MS/MS, and confirmed by western blot. Recombinant proteins were then tested for binding to each NPXY motif. The NPXY450-- (membrane distal) was found to interact with a large number of proteins, many of which only bound the tyrosine-phosphorylated form. This microdomain also bound a significant number of other proteins in the unphosphorylated state. Many of the interactions were later confirmed to be direct with recombinant proteins. The NPXY44--3 (membrane proximal) bound many fewer proteins and only to the phosphorylated form.
Author:
Publisher:
ISBN:
Category : Alzheimer's disease
Languages : en
Pages : 8
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Author: Qing Yan
Publisher: Springer Nature
ISBN: 107162573X
Category : Medical
Languages : en
Pages : 618
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Book Description
This new edition offers a state-of-the-art and integrative vision of pharmacogenomics by exploring new concepts and practical methodologies focusing on disease treatments, from cancers to cardiovascular and neurodegenerative disorders and more. The collection of these theoretical and experimental approaches facilitates problem-solving by tackling the complexity of personalized drug discovery and development. Written by leading experts in their fields for the highly successful Methods in Molecular Biology series, the book aims to provide across-the-board resources to support the translation of pharmacogenomics into better individualized health care. Authoritative and up-to-date, Pharmacogenomics in Drug Discovery and Development, Third Edition aims to aid researchers in approaching the challenges in pharmacogenomics and personalized medicine with the introduction of these novel ideas and cutting-edge methodologies.
Author: Vladimir N. Uversky
Publisher: Springer
ISBN: 9780387259185
Category : Science
Languages : en
Pages : 0
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Book Description
Research indicates that most neurodegenerative diseases, systemic amyloidoses and many others, arise from the misfolding and aggregation of an underlying protein. This is the first book to discuss significant achievements in protein structure-function relationships in biochemistry, molecular biology and molecular medicine. The authors summarize recent progress in the understanding of the relationships between protein misfolding, aggregation and development of protein deposition disorders.
Author: Velandai Srikanth
Publisher: Academic Press
ISBN: 0128096942
Category : Medical
Languages : en
Pages : 322
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Book Description
Type 2 Diabetes and Dementia details the relationship between diabetes, dementia and the future of medicine and therapeutics. Chapters range from epidemiology, clinical features, neuroimaging biomarkers, neuropathology, macrostructural and molecular mechanisms, risk assessment and prevention strategies, and the application of therapeutics. The book reflects the translational aspects of the current science in the field, with an emphasis on the display of neuroimaging and neuropathology. It contains contributions from world experts, and is ideal for clinicians and researchers in the fields of neurology, neuroscience, geriatric medicine and endocrinology. - Presents a comprehensive overview that details the relationship between diabetes, dementia and the future of medicine and therapeutics - Written for researchers and clinicians in neurology, neuroscience, geriatric medicine and endocrinology - Includes topics ranging from epidemiology, clinical features, neuroimaging biomarkers, neuropathology, macrostructural and molecular mechanisms, risk assessment, prevention strategies and therapeutic applications
Author:
Publisher: Elsevier
ISBN: 0080861431
Category : Medical
Languages : en
Pages : 223
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Book Description
Experimental Epilepsy
