Molecular Brain Research 78 (2000) 138–145 www.elsevier.com / locate / bres Research report Specific downregulation of presenilin 2 gene expression is prominent during early stages of sporadic late-onset Alzheimer’s disease a, b a,c * Pamela J. McMillan , James B. Leverenz , Daniel M. Dorsa a Department of Psychiatry and Behavioral Sciences, Box 356560, University of Washington, Seattle, WA 98195, USA b Department of Neurology, University of Washington, Seattle, WA 98195, USA c Department of Pharmacology, University of Washington, Seattle, WA 98195, USA Accepted 11 April 2000 Abstract Mutations in the presenilin genes PS1 and PS 2 cause familial Alzheimer’s disease (AD). In a previous study, we reported that PS 2 mRNA levels are decreased in the hippocampus, frontal cortex and basal forebrain of subjects with late-onset sporadic AD. In this study, we examined whether this downregulation occurs as the disease progresses from mild to severe stages or whether downregulation of PS 2 expression is an early event in AD. We used in situ hybridization histochemistry to quantify the level of expression of PS 2 message in the hippocampus of normal subjects and subjects with mild, moderate or severe AD. Several regions of the hippocampus which are sequentially susceptible to AD neuropathology as the disease progresses in severity were analyzed. We demonstrate that specific downregulation of PS 2 expression is as severe in subjects with mild AD as it is in subjects in late stages of the disease. In addition, we show that hippocampal regions that are relatively free of AD neuropathology during early stages of the disease exhibit severely compromised PS 2 mRNA levels even in mild AD cases. In contrast, PS 2 is expressed at normal levels in the cerebellum, a region which succumbs to significantly fewer AD-related insults even at very advanced stages of the disease. These results suggest that the specific downregulation of PS 2 gene expression is an early event in sporadic late-onset AD.  2000 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Degenerative disease: Alzheimer’s – other Keywords: Presenilin; Alzheimer’s disease; Hippocampus; Cerebellum; Gene expression 1. Introduction mutations in the presenilin genes, PS 1 and PS 2, as well as APP, result in the development of FAD [4,9,16, Alzheimer’s disease (AD), a devastating neurological 19,20,24,29]. The neuropathological changes in both disorder for which there is no known cure, is characterized sporadic late-onset AD and FAD are similar, suggesting by severe neuronal degeneration, neurofibrillary tangles that they share a common pathway in the etiology of the and deposits of amyloid plaques. The major component of disease [17]. Thus, although the presenilin mutations amyloid plaques is the 42-amino acid peptide Ab which is account for only 1–2% of all AD, determining the molecu- derived from the proteolytic processing of the amyloid lar basis of FAD may provide insight into the patho- precursor protein (APP) by b and g secretases. Two types physiology of the more prevalent late-onset sporadic AD. of AD have been identified. Sporadic late-onset AD Studies in our lab have focused on the possible in- accounts for the majority of AD cases and is associated volvement of presenilins in the etiology of sporadic late- with several genetic risk factors [25,26,31]. Early-onset onset AD. We and others have previously reported that familial AD (FAD) is a much more rare form in which presenilin expression in the human brain is widespread and onset generally occurs under 60 years of age. FAD primarily neuronal [14,18]. In addition, we reported that PS 2 mRNA levels are reduced in sporadic late-onset AD, suggesting that downregulation of presenilins may be *Corresponding author. Tel.: 11-206-685-8799; fax: 11-206-543- involved in the progression of the disease. A study by 9520. E-mail address: pammcm@u.washington.edu (P.J. McMillan) Takami et al. [32] supported these findings and also 0169-328X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0169-328X(00)00086-3