Brain site-specific gene expression analysis in Alzheimer's disease patients

Authors


  • BF Research Institute, Itoyoshi Building 201, 2-5-9 Doshomachi, Chuo-ku, Osaka 541-045, Japan (T. Yokota, Y. Nagai, T. Sawada, K. Heese); Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tsukuba-City, Ibaraki 305–8575, Japan (T. Yokota, T. Miyauchi); Choju Medical Institute, Fukushimura Hospital, 19-14 Aza-Yamanaka, Noyori, Toyohashi, Aichi 441-8124, Japan (H. Akatsu, Y. Tani, T. Yamamoto, K. Kosaka); Department of Molecular and Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore (M. Mishra, K. Heese).

Klaus Heese, PhD, Department of Molecular and Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore. Tel.: +65-6316-2848; fax: +65-6791-3856; e-mail: kheese@ntu.edu.sg

Abstract

Background  Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques (SPs) of aggregated amyloid-beta peptide (Aβ) and intracellular neurofibrillary tangles (NFTs). Given the critical role of neuronal transport of both proteins and organelles, it is not surprising that perturbation of microtubule-based transport may play a major role in the pathogenesis of AD.

Materials and methods  We used the cDNA subtraction methodology and in vitro neural cell culture analyses to study the meaning of the brain site-specific gene expression pattern in cerebral tissue obtained from AD patients and also from control subjects at autopsy.

Results  We observed that cytoskeleton-associated proteins were down-regulated in AD subjects. We also noted an altered expression of the microtubule-associated protein 1B (MAP1B), the heat-shock protein (HSP)-90 (a key chaperone molecule), the tripartite motif-containing proteins (TRIM)-32/37 (an anti apoptotic enzyme with ubiquitin-protein ligase activity) and the Reticulon-3 (a modulator of the amyloid-precursor-protein (APP) cleavage) in AD brains. Additional molecular- and cell-biological studies revealed that small interfering RNA (siRNA)-mediated down-regulation of MAP1B expression leads to neuronal cell death in vitro.

Conclusion  Altered expression of MAP1B, HSP90, TRIM32/37 and Reticulon-3 provides new clues by which the ubiquitin-proteasome-, the protein-chaperon- and the APP-processing systems are disturbed in AD, thus, leading to neuritic amyloid plaques and neurofibrillary tangles.

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