Charles Sanders, Ph.D., professor of Biochemistry, and colleagues in the Center for Structural Biology determined the structure of part of the amyloid precursor protein (APP) \u2013 the source of amyloid-beta, which is believed to trigger Alzheimer\u2019s disease. Amyloid-beta clumps together into oligomers that kill neurons, causing dementia and memory loss. The amyloid-beta oligomers eventually form plaques in the brain \u2013 one of the hallmarks of the disease.<\/p>\n \u201cAnything that lowers amyloid-beta production should help prevent, or possibly treat, Alzheimer\u2019s disease,\u201d Sanders said.<\/p>\n Amyloid-beta production requires two \u201ccuts\u201d of the APP protein. The first cut, by the enzyme beta-secretase, generates the C99 protein, which is then cut by gamma-secretase to release amyloid-beta. The Vanderbilt researchers used nuclear magnetic resonance and electron paragmagnetic resonance spectroscopy to determine the structure of C99, which has one membrane-spanning region.<\/p>\n They were surprised to discover what appeared to be a \u201cbinding\u201d domain in the protein<\/strong>. Based on previously reported evidence that cholesterol promotes Alzheimer\u2019s disease, they suspected that cholesterol might be the binding partner. The researchers used a model membrane system called \u201cbicelles\u201d (that Sanders developed as a postdoctoral fellow) to demonstrate that C99 binds cholesterol.<\/p>\n \u201cIt has long been thought that cholesterol somehow promotes Alzheimer\u2019s disease, but the mechanisms haven\u2019t been clear,\u201d Sanders said. \u201cCholesterol binding to APP and its C99 fragment is probably one of the ways it makes the disease more likely<\/strong>.\u201d<\/p>\n Sanders and his team propose that cholesterol binding moves APP to special regions of the cell membrane called \u201clipid rafts,\u201d which contain \u201ccliques of molecules that like to hang out together,\u201d he said.<\/p>\n Beta- and gamma-secretase are part of the lipid raft clique.<\/p>\n \u201cWe think that when APP doesn\u2019t have cholesterol around, it doesn\u2019t care what part of the membrane it\u2019s in,\u201d Sanders said. \u201cBut when it binds cholesterol, that drives it to lipid rafts, where these \u2018bad\u2019 secretases are waiting to clip it and produce amyloid-beta.\u201d<\/p>\n The findings suggest a new therapeutic strategy to reduce amyloid-beta production, he said.<\/p>\n \u201cIf you could develop a drug that blocks cholesterol from binding to APP, then you would keep the protein from going to lipid rafts. Instead it would be cleaved by alpha-secretase \u2013 a \u2018good\u2019 secretase that isn\u2019t in rafts and doesn\u2019t generate amyloid-beta.\u201d<\/p>\n Drugs that inhibit beta- or gamma-secretase \u2013 to directly limit amyloid-beta production \u2013 have been developed and tested, but they have toxic side effects. A drug that blocks cholesterol binding to APP may be more specific and effective in reducing amyloid-beta levels and in preventing, or treating, Alzheimer\u2019s disease.<\/p>\n The C99 structure had some other interesting details, Sanders said.<\/p>\n The membrane domain of C99 is curved, which was unexpected but fits perfectly into the predicted active site of gamma-secretase. Also, a certain sequence of amino acids (GXXXG) that usually promotes membrane protein dimerization (two of the same proteins interacting with each other) turned out to be central to the cholesterol-binding domain. This is a completely new function for GXXXG motifs, Sanders said.<\/p>\n \u201cThis revealing new information on the structure of the amyloid precursor protein and its interaction with cholesterol is a perfect example of the power of team science,\u201d said Janna Wehrle, Ph.D., who oversees grants focused on the biophysical properties of proteins at the National Institutes of Health\u2019s National Institute of General Medical Sciences (NIGMS), which partially funded the work. \u201cThe researchers at Vanderbilt brought together biological and medical insight, cutting-edge physical techniques and powerful instruments, each providing a valuable tool for piecing together the puzzle.\u201d<\/p>\n Sanders is proud that the studies reflect the value of basic science research and the full continuum of basic to clinical science.<\/p>\n \u201cWhen we were developing bicelles 20 years ago, no one was saying, \u2018someday these things are going to lead to discoveries in Alzheimer\u2019s disease,\u2019\u201d he said. \u201cIt was interesting basic science research that is now paying off.\u201d<\/p>\n The Vanderbilt team included lead authors Paul Barrett and Yuanli Song, Ph.D., as well as Wade Van Horn, Ph.D., Eric Hustedt, Ph.D., Johanna Schafer, Arina Hadziselimovic and Andrew Beel. The research was supported by grants from NIGMS (GM080513) and the Alzheimer\u2019s Association.<\/p><\/blockquote>\n","protected":false},"excerpt":{"rendered":" From the Vanderbilt University press release via Newswise: The molecular structure of a protein involved in Alzheimer\u2019s disease \u2013 and the surprising discovery that it binds cholesterol \u2013 could lead to new therapeutics for the disease, Vanderbilt University investigators report in the June 1 issue of the journal Science. Charles Sanders, Ph.D., professor of Biochemistry,… <\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"neve_meta_sidebar":"","neve_meta_container":"","neve_meta_enable_content_width":"","neve_meta_content_width":0,"neve_meta_title_alignment":"","neve_meta_author_avatar":"","neve_post_elements_order":"","neve_meta_disable_header":"","neve_meta_disable_footer":"","neve_meta_disable_title":"","footnotes":""},"categories":[10,4,6],"tags":[195,42,194,49],"class_list":["post-3344","post","type-post","status-publish","format-standard","hentry","category-health","category-memory","category-neuroscience","tag-alzheimers","tag-brain","tag-dementia","tag-mental-health"],"_links":{"self":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts\/3344","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/comments?post=3344"}],"version-history":[{"count":2,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts\/3344\/revisions"}],"predecessor-version":[{"id":3369,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts\/3344\/revisions\/3369"}],"wp:attachment":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/media?parent=3344"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/categories?post=3344"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/tags?post=3344"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}![\"\"](\"http:\/\/therapytoronto.ca\/images\/blogpics\/Brain.jpg\" "\\"brain\\"")
The molecular structure of a protein involved in Alzheimer\u2019s disease \u2013 and the surprising discovery that it binds cholesterol \u2013 could lead to new therapeutics for the disease<\/strong>, Vanderbilt University investigators report in the June 1 issue of the journal Science<\/em>.<\/p>\n