Lifespan Profiles of Alzheimer's Disease-Associated Genes and Products in Monkeys and Mice

Article type: Research Article

Authors: Dosunmu, Remi^a | Wu, Jinfang^a | Adwan, Lina^a | Maloney, Bryan^d | Basha, Md. Riyaz^a | McPherson, Christopher A.^b | Harry, G. Jean^b | Rice, Deborah C.^c | Zawia, Nasser H.^{a; *} | Lahiri, Debomoy K.^{d; *}

Affiliations: [a] Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA | [b] National Institutes of Health, Research Triangle Park, NC, USA | [c] Maine Department of Health and Human Services, Augusta, ME, USA | [d] Department of Psychiatry and of Medical & Molecular Genetics, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence: [*] Corresponding author: Dr. D.K. Lahiri, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Tel.: +1 317 274 2706; Fax: +1 317 274 1365; E-mail: [email protected]. Or Dr. N.H. Zawia, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. Tel.: +1 401 874 5909; Fax: +1 401 874 5787; E-mail: [email protected].

Abstract: Alzheimer's disease (AD) is characterized by plaques of amyloid-β (Aβ) peptide, cleaved from amyloid-β protein precursor (AβPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AβPP mRNA, AβPP protein, and Aβ levels in rodents and primates. We also tracked a transcriptional regulator of the AβPP gene, specificity protein 1 (SP1), and the β amyloid precursor cleaving enzyme (BACE1). In mice, AβPP and SP1 mRNA and their protein products were elevated late in life; Aβ levels declined in old age. In monkeys, SP1, AβPP, and BACE1 mRNA declined in old age, while protein products and Aβ levels rose. Proteolytic processing in both species did not match production of Aβ. In primates, AβPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Aβ levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases.

Keywords: Amyloid-β protein precursor (AβPP), amyloidogenesis, BACE1, development, primates, rodents, specificity protein 1 (SP1), transcription

DOI: 10.3233/JAD-2009-1138

Journal: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 211-230, 2009