Enhanced Accumulation of Phosphorylated a-Synuclein in Double Transgenic Mice Expressing Mutant b-Amyloid Precursor Protein and Presenilin-1 Tomoko Kurata, 1 Takeshi Kawarabayashi, 2 Tetsuro Murakami, 1 Kazunori Miyazaki, 1 Nobutoshi Morimoto, 1 Yasuyuki Ohta, 1 Yasushi Takehisa, 1 Makiko Nagai, 1 Masaki Ikeda, 3 Etsuro Matsubara, 4 David Westaway, 5 Peter St. George Hyslop, 5 Yasuo Harigaya, 6 Tatsushi Kamiya, 1 Mikio Shoji, 2 and Koji Abe 1 * 1 Department of Neurology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan 2 Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan 3 Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan 4 Department of Alzheimer’s Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Japan 5 Departments of Medicine (Neurology) and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada 6 Department of Neurology, Maebashi Red Cross Hospital, Maebashi, Japan A recent report showed that the accumulation of a-syn- uclein (a-syn) was detected in the brains of one-third of Alzheimer’s disease and Down syndrome patients. However, the relationship between amyloid-b protein (Ab) and a-syn remains unclear. We analyzed the rela- tion between the mutation of presenilin-1 (PS-1) and the pathological features of b-amyloidosis and a-synu- cleinopathy. We generated doubly transgenic mice overexpressing mutant b-amyloid precursor protein (bAPP; Tg2576) and mutant PS-1 (PS1L286Vtg; line 198) and analyzed 19 double Tg bAPP þ /PS þ mice at 5– 23 months (young to old), 23 age-matched single Tg bAPP þ /PS – mice, and 11 non-Tg littermates. Immuno- histochemical comparison was performed in these three groups by counting the area and the number of a-syn- or phosphorylated a-syn (pa-syn)-positive dys- trophic neurites per plaque (ASPDN, pASPDN). The acceleration of Ab pathology was found with earlier onset and exaggerated numbers in double Tg bAPP þ / PS þ compared with single Tg bAPP þ /PS – mouse brains. The accumulation of ASPDN and pASPDN was also accelerated in double Tg bAPP þ /PS þ compared with single Tg bAPP þ /PS – mouse brains, especially in pASPDN. The number and area of a-syn and pa-syn, and the ratio of pa-syn positive neurites were signifi- cantly higher in double Tg bAPP þ /PS þ than in single Tg bAPP þ /PS – mouse brains in middle-aged and old groups. Additional overexpression of mutant PS-1 accelerated Ab-induced a-synucleinopathy and further facilitated the phosphorylation of a-syn, suggesting a direct association between mutant PS-1 and phospho- rylation of a-syn. V V C 2007 Wiley-Liss, Inc. Key words: Alzheimer’s disease; transgenic mouse; presenilin-1; synuclein; phosphorylation Alzheimer’s disease (AD) is one of the most com- mon neurodegenerative disorders in senile dementia and is a medical, social, and economic problem because of the increase in the elderly population in modern society. About 5% of people over 65 years old suffer from de- mentia. AD brains are invariably characterized by initial amyloid b protein (Ab) amyloidosis by extracellular dep- osition of Ab42 and Ab40 and subsequent tauopathy characterized by the intracellular accumulation of neuro- fibrillary tangles (NFT) comprising abnormal aggregates of phosphorylated tau (ptau). AD is most likely associ- ated with genes and environmental factors. Mutations in presenilin-1 (PS-1) and presenilin-2 (PS-2) are the most common cause of familial AD, 50% of which is associated with PS-1 mutation (Cruts and Van Broeckhoven, 1998). Because familial AD-linked Contract grant sponsor: Ministry of Education, Science, Culture and Sports of Japan; Contract grant sponsor: Ministry of Health and Welfare of Japan. *Correspondence to: Prof. Koji Abe, Department of Neurology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558 Japan. E-mail: toko11@cc.okayama-u.ac.jp Received 19 December 2006; Revised 28 February 2007; Accepted 8 March 2007 Published online 24 May 2007 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.21352 Journal of Neuroscience Research 85:2246–2252 (2007) ' 2007 Wiley-Liss, Inc.