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Alzheimer's Disease Research - Current Award

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Tae-Wan Kim, Ph.D.

Columbia University
New York, NY

Title: Modulation of BACE1 by a Novel Sorting Nexin
Non-Technical Title: BACE1 Trafficking and Alzheimer's Disease

Duration: April 1, 2008 - March 31, 2011
Award Type: Standard
Award Amount: $265,000


Summary:

This study will investigate the mechanism underlying the regulation of BACE1 trafficking and beta-amyloid generation in neurons by a novel sorting nexin. Gaining insight into these cellular mechanisms will lead to development of novel therapeutic approaches for preventing or treating AD.

Details:


Aberrant trafficking of Alzheimer's disease (AD)-associated molecules, such as beta-amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1), has been extensively implicated in the neuropathogenesis of AD. BACE1 mediates the first of two cleavage events of APP to yield amyloid beta-peptide (A-beta). Recent studies suggest that aberrant regulation of molecular components of the endosome and trans-Golgi network (TGN) may contribute to the enhanced A-beta levels associated with AD. We discovered that a novel sorting 'nexin', a member of the family of trafficking proteins that bind phospholipids, binds BACE1 and regulates the cleavage of APP. Our proposed studies will investigate the mechanism underlying the regulation of BACE1 trafficking and beta-amyloid generation in neurons by this novel sorting nexin. Gaining insight into these cellular mechanisms will lead to development of novel therapeutic approaches for preventing or treating AD.

Publications:

Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. (2010) Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Mar 30. PubMed Icon Google Scholar Icon

This paper reports new regulator of BACE1, a key proteolytic enzyme in Alzheimer's disease.

Progress Updates:

Aberrant trafficking of Alzheimer’s disease (AD)-associated proteins and peptides, such as the beta-amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1), has been extensively implicated in the pathogenesis of AD. BACE1 mediates the first of two “cuts” to APP to yield amyloid beta-peptide (A-beta). Recent studies suggest that problems with the trafficking of proteins within the cell protein-processing sacs, called the endosome and trans-Golgi network (TGN), may contribute to the enhanced A-beta levels associated with AD. We discovered that a novel sorting protein called “sorting nexin 6” (SNX6), a member of the family of trafficking proteins that bind phospholipids, binds BACE1 and regulates the beta-site “cut” to APP. We investigated the mechanism underlying the regulation of BACE1 trafficking and beta-amyloid generation in neurons by SNX6.

We found that SNX6 is associated with BACE1 in the TGN and is expressed in brain cells. Reduction of SNX6 levels enhanced BACE1-mediated cleavage of APP without influencing other ways of cleaving APP. This shows that there is an inverse relationship between SNX6- and BACE1-mediated cleavage of APP. Furthermore, analysis of cell surface BACE1 protein trafficking from endosomes to the TGN revealed that SNX6 facilitates this transport. Thus, these data illustrated a novel cellular pathway for BACE1 regulation by which SNX6 negatively modulates BACE1-mediated cleavage of APP by regulating the trafficking of BACE1. Gaining insight into these cellular mechanisms will lead to the development of novel therapeutic approaches for preventing or treating AD.