Cerebral deposition of beta-amyloid peptides (AB) is one of the pathological hallmarks of Alzheimer's disease. AB is generated by sequential proteolysis of amyloid precursor protein (APP) by BACE1 and g-secretase. g-secretase is a multimeric protein complex made of four main subunits, namely PS1 (or PS2), nicastrin, PEN2 and APH-1, and a few regulatory subunits including CD147 and p23 (also referred to asTMP21). PS1 is thought to function as the catalytic subunit of g-secretase complex. Post-translational maturation and stability of the four core subunits of g-secretase are mutually regulated, and each of them is indispensable for functional enzyme activity. On the other hand, diminution of CD147 or p23 expression increases AB production, suggesting that these proteins negatively regulate g-secretase processing of APP. The specific mechanisms by which p23 modulates g-secretase cleavage of APP remain undetermined. Studies outlined in this proposal address the function of p23 in trafficking and g-secretase processing of APP in cultured cells and in mouse brains Specifically, we propose to elucidate the functional interaction between p23 and g-secretase subunits so that we can better understand the mechanisms by which p23 negatively regulates AB production. We will define the structural domains essential for p23's influence on APP trafficking and AB production, and investigate p23 modulation of AB deposition using p23 transgenic mice and p23 conditional knockout mice. Finally, we will investigate the details on p23's role in secretory and endocytic trafficking of APP and examine the relationship between Golgi morphology and AB production. Our investigation uses a combination of biochemical, molecular and cell biology techniques to accomplish the following specific aims.
Aim 1 : To study the functional interaction between p23 and g-secretase.
Aim 2 : To investigate p23 regulation of AB production and deposition in mouse brain.
Aim 3 : To determine the mechanisms linking p23 function with APP trafficking and g-secretase processing. Our studies address issues that are central to molecular Alzheimer's disease pathogenesis. We seek to investigate a novel aspect of g-secretase modulation by p23 that impacts on AB production. Our studies have the potential to uncover significant insights on p23 regulation of APP trafficking and AB production, and may lead to the development of p23-based novel therapeutic strategies aimed reducing AB burden by selective inactivation of g-secretase function in APP processing.
Alzheimer's disease (AD) is the major cause of dementia in the elderly, afflicting more than 50% of the population over 80 years of age;presently 5.1 million Americans suffer from this devastating disorder. AD patients as well as aged individuals accumulate beta-amyloid peptides as deposits in brain, called senile plaques. Using cultured cells, transgenic mice, and conditional knockout mice as experimental models we investigate the function a protein called p23 in regulating beta-amyloid production and deposition. Our studies will be critical to develop novel rational AD therapeutics aimed at reducing beta-amyloid burden in the brain.
|Buggia-Prévot, Virginie; Fernandez, Celia G; Riordan, Sean et al. (2014) Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase. Mol Neurodegener 9:1|
|Udayar, Vinod; Buggia-Prévot, Virginie; Guerreiro, Rita L et al. (2013) A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of ?-amyloid production. Cell Rep 5:1536-51|
|Zeiger, William; Vetrivel, Kulandaivelu S; Buggia-Prévot, Virginie et al. (2013) Ca2+ influx through store-operated Ca2+ channels reduces Alzheimer disease ?-amyloid peptide secretion. J Biol Chem 288:26955-66|
|Maulik, Mahua; Thinakaran, Gopal; Kar, Satyabrata (2013) Alterations in gene expression in mutant amyloid precursor protein transgenic mice lacking Niemann-Pick type C1 protein. PLoS One 8:e54605|
|Buggia-Prévot, Virginie; Fernandez, Celia G; Udayar, Vinod et al. (2013) A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease A? production. Cell Rep 5:1552-63|
|Zeiger, William; Ito, Daisuke; Swetlik, Carol et al. (2011) Stanniocalcin 2 is a negative modulator of store-operated calcium entry. Mol Cell Biol 31:3710-22|
|Vetrivel, Kulandaivelu S; Barman, Arghya; Chen, Ying et al. (2011) Loss of cleavage at ?'-site contributes to apparent increase in ?-amyloid peptide (A?) secretion by ?-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein. J Biol Chem 286:26166-77|
|Gong, Ping; Roseman, Jelita; Fernandez, Celia G et al. (2011) Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice. Mol Neurodegener 6:87|
|Meckler, Xavier; Roseman, Jelita; Das, Pritam et al. (2010) Reduced Alzheimer's disease ýý-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin. J Neurosci 30:16160-9|
|Gong, Ping; Vetrivel, Kulandaivelu S; Nguyen, Phuong D et al. (2010) Mutation analysis of the presenilin 1 N-terminal domain reveals a broad spectrum of gamma-secretase activity toward amyloid precursor protein and other substrates. J Biol Chem 285:38042-52|
Showing the most recent 10 out of 28 publications