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The mechanism of the low-density lipoprotein receptor- related protein (LRP) in the production of amyloid-[Beta] peptide

  • Author(s): Chen, Eunice Chungyu
  • et al.
Abstract

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

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