Alzheimer's Disease Research - Completed Award

	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.

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

Finan GM, Okada H, Kim T-W. (2011) BACE1 Retrograde Trafficking is Uniquely Regulated by the Cytoplasmic Domain of Sortilin. J. Biol. Chem. 286, 12602-12616.

Di Paolo G, Kim T-W. (2011) Linking lipids to Alzheimer's disease: cholesterol and beyond. Nature Rev. Neurosci. 12, 284-296.

Progress Updates:

Improper trafficking, or sorting, of Alzheimer's disease (AD)-associated proteins, such as beta-amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1), is associated with the development of AD. BACE1 mediates the first of two cleavage events of APP to yield beta-amyloid peptide.  Recent studies suggest that problems with the regulation of the endosome and trans-Golgi network, parts of the cell that are involved in protein sorting, may contribute to the increased beta-amyloid levels associated with AD. Dr. Tae-Wan Kim and colleagues discovered that a member of the phospholipid (fat)-binding sorting nexin family, called Snx6, also binds BACE1 and regulates both its transport within the cell and its ability to complete beta-site cleavage of APP. In addition, these researchers determined that reduction of Snx6 can promote BACE1 generation of beta-amyloid in nerve cells. Dr. Kim’s discoveries about these new cell sorting mechanisms may lead to the development of new preventions or treatments for AD.