The Faculty

Focus

Cellular and molecular biology of Alzheimer’s disease

Education

Ph.D.,  University of Guelph, Canada   1992

M.S.,    Madurai Kamaraj University
             Madurai, India     1987

B.A.,     Madurai Kamaraj University
             Madurai, India     1985

Research Summary

Alzheimer’s disease (AD) is the major cause of dementia in the elderly and the seventh-leading cause of death. This devastating disorder for which no cure is presently available, strikes someone in the United States every 70 seconds. More than half the population over 80 years of age suffers from AD. The number of Americans living with AD at present is estimated at 5.3 million. As the lifespan of humans continues to increase in industrialized societies and emerging economies, AD is becoming an ever-increasing social burden for the health care system and emotional burden for the immediate family members.

A little over one hundred years ago, Alois Alzheimer, a German psychiatrist and neuropathologist, first presented the case study of patient who suffered from the devastating illness that now bears his name. In a paper published in 1907, Alzheimer wrote: "Scattered through the entire cortex, especially in the upper layers, one found miliary foci that were caused by the deposition of a peculiar substance." Eighty years later, the "peculiar substance" was characterized as ~38-42 amino acid-long beta-amyloid peptides (Ab), which are derived from a larger type I transmembrane protein, termed amyloid precursor protein (APP). Cerebral deposition of Ab peptides in senile plaques is causally linked to AD. It is well established that Ab is associated with neuronal death and consequent memory loss.

The overarching goal of my research is to develop a better understanding of the molecular and cellular mechanisms that regulate Ab production. Specifically, my lab has been investigating the cell biology of two proteases, termed BACE1 and g-secretase, which sequentially cleave APP to generate Ab. BACE1 is a type I transmembrane aspartyl protease, whereas g-secretase is a multiprotein transmembrane complex made of the catalytic subunit presenilin (PS1 or PS2) and three other integral subunits: nicastrin, APH-1 and PEN-2. We use cultured neuronal and non-neuronal cell lines, primary neurons, knock out mice and transgenic mouse models of AD pathogenesis in our investigations.

In recent years, we have investigated amyloidogenic processing of APP in cholesterol- and sphingolipid-rich membrane microdomains, termed lipid rafts. Ongoing investigations focus on: 1) the role of S-palmitoylation on BACE1 and g-secretase microdomain localization and trafficking in cultured neurons and in mouse brain; 2) advanced live cell imaging of BACE1 trafficking and transport; 3) generating and characterizing animal models of p23, a negative regulator of Ab production, etc. In addition, we have been interested in the physiological functions of Stanniocalcin 2, a protein whose expression is induced by cellular adaptive response to protein misfolding stress, termed the unfolded protein response. We have recently uncovered a molecular function for Stanniocalcin 2 in cellular calcium homeostasis and are now exploring the potential involvement of calcium homeostasis in Alzheimer’s disease pathogenesis using cell culture and animal models.

Selected Papers

Vetrivel KS, Barman A, Chen Y, Nguyen PD, Wagner SL, Prabhakar R, and Thinakaran G: Loss of cleavage at beta’-site contributes to the apparent increase of Abeta secretion by BACE1-GPI processing of APP. J. Biol. Chem. 286: 26166–26177, 2011.

Zeiger W, Ito D, Swetlik C, Oh-hora M, Villereal ML, and Thinakaran G: Stanniocalcin 2 is a negative modulator of store-operated calcium entry. Mol. Cell Biol. 18: 3710-22, 2011.

Meckler X, Roseman, J, Das P, Cheng H, Pei S, Keat M, Kassarjian B, Golde TE, Parent AT, and Thinakaran G: Reduced Alzheimer’s disease β-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin. J. Neurosci. 30: 16160-16169, 2010.

Gong P, Cheng H, Vetrivel KS, Nguyen PD, Kounnas MZ, Thinakaran G: Mutation analysis of the presenilin 1 N-terminal domain reveals a broad spectrum of γ-secretase activity towards APP and other substrates. J. Biol. Chem. 285: 38042-38052, 2010.

Vetrivel KS, Meckler X, Chen Y, Nguyen PD, Kounnas MZ and Thinakaran G: Alzheimer disease Ab production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts. J. Biol. Chem. 284:3793-803, 2009.

Chen H, Vetrivel KS, Drisdel R, Li T, Carter M, Gong P, Chen Y, Nguyen PD, Placania L, Li Y-M, Wong PC, Green WN, Kounnas MZ and Thinakaran G: S-palmitoylation of g-secretase subunits. J. Biol. Chem. 284:1373-1384, 2009.

Vetrivel KS, Kodam A, Chen Y, Parent A, Kar S and Thinakaran G: Localization and regional distribution of p23/TMP21 in the brain. Neurobiol. Dis. 32:37-49, 2008.

Vetrivel KS, Zhang X, Meckler X, Cheng H, Lee S, Gong P, Chen Y, Iwata| N, Parent A, Saido TC, Li Y, Sisodia SS, Thinakaran G: Evidence that CD147 modulation of Ab levels is mediated by extracellular degradation of secreted Aß. J. Biol. Chem. 283:19489-98, 2008.

Vetrivel KS, Gong P, Bowen JW, Cheng H, Chen Y, Carter M, Nguyen PD, Placanica L, Wieland FT, Li YM, Kounnas MZ and Thinakaran G: Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism. Mol Neurodegener. 2007 Feb 8;2(1):4.

Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, Parent AT, Sisodia SS and Thinakaran G: Spatial segregation of g-secretase and substrates in distinct membrane domains. J. Biol. Chem. 280:25892-25900, 2005.

Parent AT, Barnes NY, Taniguchi Y, Thinakaran G, and Sisodia SS: Presenilin attenuates receptor-mediated signaling and synaptic function. J. Neurosci. 25:1540-1549, 2005.

Ito D, Walker JR, Thompson CS, Moroz I, Lin W, Veselits ML, Hakim AM, Fienberg AA, and Thinakaran G: Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties. Mol. Cell. Biol. 24:9456-69, 2004.

Vetrivel KS, Cheng H, Sakurai T, Li T, Nukina N, Wong PC, and Thinakaran G: Association of gamma-secretase complex with lipid raft microdomains in post-Golgi and endosomes membranes. J. Biol. Chem. 279:44945-44954, 2004.

Sato N, Urano F, Leem J-Y, Kim SH, Donoviel D, Bernstein A, Li M, Lee AS, Ron D, Veselits ML, Sisodia SS and Thinakaran G: Upregulation of BiP and CHOP by the unfolded protein response is independent of presenilin expression. Nature Cell Biol. 2:863-870, 2000.

Vetrivel KS, Barman A, Chen Y, Nguyen PD, Wagner SL, Prabhakar R, Thinakaran G. (2011) Loss of cleavage at b'-site contributes to the apparent increase in Ab secretion by BACE1-GPI processing of amyloid precursor protein. J. Biol. Chem. 286: 26166–26177. PMCID: PMC3138254

Zeiger W, Ito D, Swetlik C, Oh-hora M, Villereal ML, and Thinakaran G. (2011) Stanniocalcin 2 is a negative modulator of store-operated calcium entry. Mol. Cell Biol. 18: 3710-3722. PMID: 21746875 PMC 3165734

Gong P, Roseman J, Fernandez CG, Vetrivel KS, Bindokas VP, Zitzow LA, Kar S, Parent AT, and Thinakaran G. (2011) Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice. Mol Neurodegener. 6:87. PMCID: PMC3259059

Deyts C, Vetrivel KS, Shepherd YM, Dupré DJ, Thinakaran G and Parent AT: Novel Gαs-protein signaling associated with membrane-tethered APP intracellular domain. J. Neurosci. 32:1714-1729, 2012. PMC3567462

Maulik M, Thinakaran G, Kar S. (2013) Alterations in gene expression in mutant amyloid precursor protein transgenic mice lacking Niemann-Pick type C1 protein.  PLoS One. 8(1):e54605 PMCID: PMC3558508