Interaction of Pin1 with phosphorylated tau and APP: Implications for Alzheimer's disease

Date

2007

Authors

Ramakrishnan, Pankajavalli

Journal Title

Journal ISSN

Volume Title

Publisher

ProQuest Dissertations & Theses

YU Faculty Profile

Abstract

Alzheimer's Disease (AD), a common dementing illness begins with memory loss, and gradually progresses to global cognitive decline. Neuropathologically, AD is characterized by intraneuronal accumulation of hyperphosphorylated tau into neurofibrillary tangles (NFTs), extracellular beta-amyloid (Abeta) deposition, and neuronal loss. Their contribution to AD pathogenesis might lie in exploring the mitotic hypothesis of AD.;Aberrant reactivation of mitotic regulators in post-mitotic neurons in AD brains was recognized recently. Tau's phosphorylation profile in dividing cells resembles that seen in AD. Hyperphosphorylation and conformational changes on tau precede paired helical filaments (PHFs) formation, which aggregate into tangles. How do these modifications give rise to PHFs?;APP, Abeta's precursor, is phosphorylated at Thr668 in dividing cells and in AD brains. How this phosphorylation modulates Abeta levels is poorly understood. Cell cycle dysregulation in AD might explain why dividing cells escape tangle formation, exuberant Abeta deposition, and cell death, but not post-mitotic neurons in AD.;Pin1, a phosphorylation dependent prolyl-isomerase and a mitotic regulator binds to mitotic phosphoproteins on pSer-Pro or pThr-Pro motifs and affects their function by cis/trans isomerization of the peptidyl-prolyl bond. Early investigations recognized that Pin1 could bind to pThr231-Pro 232 tau, and pThr668-Pro669 APP following their phosphorylation in vitro. Whether Pin1 associated with these two phosphoproteins in AD brains and affected their functions was unclear.;Hence, this thesis was undertaken. Immunohistochemically, Pin1 in AD brains co-localized with a subset of conformationally altered tau phosphorylated at Thr231. Biochemically, Pin1 was shown to interact with pThr 231 tau in AD brains. In cell culture, Pin1 overexpression increased the amount of conformationally altered, and Sarkosyl insoluble tau.;Likewise, Pin1 co-localized with pThr668 APP in AD brains. Biochemically, Pin1 and pThr668 APP were shown to interact in AD brains and in cells. In cells overexpressing Pin1 and wt APP, Abeta levels were decreased, but not in cells overexpressing Pin1 and T668A APP, thus implicating the need for APP phosphorylation at Thr668 for this effect. Together, these results implicate Pin1 in AD pathogenesis. Further investigation might reveal insights relevant for developing rational therapeutic strategies.

Description

Keywords

Neurosciences., Pathology.

Citation

Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1470.;Advisors: Peter Davies.