Cellular and Molecular Biology of Alzheimer’s Disease

For the past several years, my research efforts have been directed towards understanding the molecular events that underly the pathogenesis of Alzheimer’s disease (AD).  AD, a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly, effecting ~7 - 10% of individuals over 65 years of age.  The prevalence of this disease increases to 40% in persons over 80 years of age.  Approximately 5 - 10 % of AD, classified as early-onset familial AD (FAD) (age of onset < 60 years), is inherited in an autosomal dominant manner and in some of these pedigrees, mutations in genes encoding the amyloid precursor protein (APP), presenilin 1(PS1) and presenilin 2 (PS2) cosegregate with FAD.  Mutations in PS1/PS2 account for the majority of the cases of FAD. 

Pathological lesions called senile plaques found in the brains of AD patients contain extracellular deposits of 40-42 amino acid-long peptides, termed b-amyloid (Ab). Aβ holds a central position in AD pathogenesis; it is generated by sequential endoproteolytic processing of amyloid precursor protein (APP) by BACE and γ-secretase.  BACE is a transmembrane aspartyl protease and γ-secretase is a multiprotein complex containing presenilin 1 (PS1) or presenilin 2 (PS2), nicastrin, APH-1 and PEN-2.  FAD-linked APP and PS1 variants enhance the production of highly amyloidogenic Ab42 peptides.  The precise mechanisms involved in g-secretase cleavage of APP, and the manner in which FAD-linked mutations favor the production of Ab42 remain unclear. 

There has been considerable epidemiological interest in the relationship between cholesterol and susceptibility to AD.  We are particularly interested in the cell biology of g-secretase and amyloidogenic processing of APP in cholesterol- and sphingolipid-rich membrane microdomains, termed lipid rafts.  In addition, we are also investigating the role of presenilins in synaptic function using cell biology, electrophysiology, and live imaging strategies.  Our goal is to uncover information critical for the development of rational therapeutic strategies for the treatment of AD.

Neuronal Stress Response

 In diseases such as triplet disorders, and prion diseases, mutations in specific genes lead to misfolding of the encoded protein products and other cellular proteins.  Thus, regardless of the etiology, several neurodegenerative diseases are characterized by the accumulation of misfolded proteins within the secretory pathway, cytoplasm or nucleus, and the association between protein aggregation and neurodegenerative diseases is an emerging field of study.  My lab is interested in protein folding stress within the secretory pathway.  We are investigating the ER stress-related gene expression with the aim of identifying common features involved in hypoxic and ischemic neuronal damage, aging, and neurodegeneration.  These investigations utilize a variety of cell culture systems and well-characterized transgenic mouse models of FAD.  Our goal is to characterize the cellular and molecular cascade of early events that lead to the etiopathogenesis of AD and other neurodegenerative disorders.

Selected Publications

Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, Parent AT, Sisodia SS and Thinakaran G: Spatial segregation of gamma -secretase and substrates in distinct membrane domains. J Biol Chem. 2005, in press. May 10; [Epub ahead of print] PMID: 15886206.

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.

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

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.

Thinakaran G, Parent AT: Identification of the role of presenilins beyond Alzheimer’s disease. Pharmacol. Res. 50: 411-418, 2004.

Takasugi N, Tomita T, Tsuruoka M, Hayashi I, Takahashi Y, Thinakaran G, and Iwatsubo T: Differential Roles of Presenilin Cofactors in the Formation and Function of γ-Secretase Complex. Nature 422: 438-441, 2003.

Leem J-Y, Saura CA, Pietrzik, C, Christianson J, Wanamaker C, King LT, Veselits ML, Tomita T, Gasparini L, Iwatsubo T, Xu H, Green W, Koo EH, and Thinakaran G.  A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface.  Neurobiol. Dis. 11: 64-82, 2002.

Leem JY, Vijayan S, Han P, Cai D, Machura M, Lopes KO, Veselits ML, Xu H, Thinakaran G. Presenilin 1 is required for maturation and cell surface accumulation of nicastrin. J Biol Chem. 277: 19236-40, 2002.

Siman R, Flood DG, Thinakaran G, Neumar RW.  Endoplasmic reticulum stress-induced cysteine protease activation in cortical neurons: effect of an Alzheimer's disease-linked presenilin-1 knock-in mutation.  J Biol Chem. 276: 44736-43, 2001.

Sato N, Urano F, Yoon Leem J, Kim SH, Li M, Donoviel D, Bernstein A, Lee AS, Ron D, Veselits ML, Sisodia SS, Thinakaran G.  Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression.  Nat Cell Biol. 212: 863-70, 2000.