The neurofibrillary tangles and senile plaques in Alzheimer's disease (AD) consist of the microtubule-associated protein tau in a hyperphosphorylated state, and A-beta, a fragment of the amyloid precursor protein (APP), respectively. Phosphorylation of tau and APP and production of amyloidogenic fragments are features of both AD neurons and normal mitotic cells. Although phosphorylation on serine or threonine residues preceding proline regulates the tau function and APP processing, little is known about what phosphorylation actually does and how it is involved in the pathogenesis of AD. Proline is important for determining protein structure because it exists in cis or trans conformation and can put kinks into a polypeptide chain. Recently, we have shown that phosphorylation on serine/threonine-proline motifs restrains cis/trans prolyl isomerization, and also creates binding sites for the WW domain of the prolyl isomerase Pin 1. The binding of the WW domain with phosphoproteins determines the localization of Pin1 in cells. Pin1 also has unique enzymatic activity that specifically isomerizes phosphorylated serine/threonine-proline bonds, and regulates the function of a defined subset fo mitosis-specific phosphoproteins, including tau. Pin1 restores the biological function of phosphorylated tau directly or indirectly by promoting dephosphorylation because the phosphatases, such as PP2A, dephosphorylate only the trans phosphorylated serine/threonine-proline isomer. Significantly, Pin1 is sequestered into the tangles and depleted in AD brains. Since depletion of Pin1 affects protein dephosphorylation, and induces mitotic arrest and apoptosis, sequestration of Pin1 may be an important factor for tau hyperphosphorylation, tangle formation and neuronal loss. Our preliminary results showed that Pin1 also binds only the phosphorylated APP with a high affinity. Therefore, we have hypothesized that Pin1 may play an important role in some pathological changes of AD. To test this hypothesis, we first plan to examine the effect of Pin1 on the biological activity of phosphorylated tau by various tau kinases or tau present in the neurofibrillary tangles, and to elucidate how Pin1 restores the biological activity of phosphorylated tau. Next, we will evaluate the interaction between Pin1 and phosphorylated APP, and determine its role in APP processing and A-beta secretion. Finally, we will examine the effects of altering the Pin1 function on the tau pathology and other neuronal phenotype of AD in cultured cells, and in animals using tau transgenic mice and Pin1 knockout mice that have been generated and provided to us. These studies should eventually help elucidate the molecular mechanisms of the pathogenesis of AD, and may have novel implications for their prevention and therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017870-02
Application #
6497206
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Miller, Marilyn
Project Start
2001-03-02
Project End
2006-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$212,500
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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