Original Article Long-term oral intake of aluminium or zinc does not accelerate Alzheimer pathology in Ab PP and Ab PP/tau transgenic mice Haruhiko Akiyama, 1 Masato Hosokawa, 1 Fuyuki Kametani, 1 Hiromi Kondo, 1 Momoko Chiba, 4 Masako Fukushima 2 and Takeshi Tabira 3 1 Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, 2 Department of Human Life Science, Showa Women’s University, 3 Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo University,Tokyo and 4 Department of Pharmacology, International University of Health and Welfare, Tochigi, Japan Whether or not the oral intake of metals such as aluminium (Al) and zinc (Zn) is a risk for Alzheimer’s disease (AD) has been a matter of controversy. Lack of AD pathology in patients with Al encephalopathy indicates Al does not cause AD. On the other hand, some epidemiological studies have suggested high Al increases the occurrence of AD. Our purpose is to test if high Al in drinking water is a risk factor for AD. We administered Al and Zn in drinking water to Tg2576, a transgenic mouse model for amyloid b-protein (Ab) deposition with the Ab precursor protein (AbPP) mutations (K670N/M671L), and Tg2576/ tau(P301L), a model for Ab and tau deposition. Deionized water was given to the control Tg2576 and Tg2576/tau. After administration for 4–10 months of approximately 100 mg/kg body weight Al or Zn per day, we were not able to find by quantitative immunohistochemical analyses dif- ferences in the deposition of Ab and tau between the treated and untreated groups. Nor did the Al or Zn treat- ment affect the amount of soluble Ab and Ab*56, an Ab oligomer, measured by ELISA or immunoblot. The oral intake of excess Al or Zn does not accelerate AD pathol- ogy in the transgenic mouse models for Ab and tau accu- mulation. Such results do not seem to support the notion that excessive oral intake of Al or Zn is a risk factor for AD. Key words: Ab, amyloid, drinking water, risk, tau. INTRODUCTION Alzheimer’s disease (AD) is the major cause of dementia in elderly people. AD is characterized neuropathologically by an abundance of senile plaques and neurofibrillary tangles (NFT), which are now recognized as abnormal accumula- tions of amyloid b-protein (Ab) and phosphorylated tau protein (tau), respectively. Deposition of Ab and tau pre- cedes by years the clinical manifestation of dementia. Known genetic abnormalities that cause familial AD have been shown to increase the accumulation of Ab in the brain. This evidence has led to the Ab cascade hypothesis of AD. One of the familial AD genes is the Ab precursor protein (AbPP). Ab is accumulated in transgenic mice that carry human AbPP with familial AD mutations. Double trans- genic mice that carry mutated AbPP and presenilin-1, another familial AD gene, develop Ab accumulation much earlier than single AbPP transgenic mice. However, these transgenic mice lack NFT formation. Requirement of an additional tau mutation for AbPP transgenic mice to form NFT 1 suggests that Ab accumulation is an accelerating factor that enhances a tau abnormality which is primarily caused by some distinct, age-related factors. Such a notion is supported by the occurrence of tangle-only dementia, which is similar to AD except for the absence of significant Ab deposits and a higher age of onset with slower progression than AD 2 . Recently, a report on the long-term follow-up of the phase II study of Ab vaccination (AN1792) described the progression of dementia in association with heavy NFT formation but with variably reduced Ab deposition. 3 While most efforts to overcome AD are now focusing on the reduction of the abnormal accumulation of Ab and tau, studies that suggest a role for aluminium or other metals in Correspondence: Haruhiko Akiyama, Head, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikiatazawa, Setagaya-ku, Tokyo 156-8506, Japan. Email: akiyama-hr@igakuken.or.jp Received 9 August 2011; revised and accepted 13 October 2011. Neuropathology 2011; ••, ••–•• doi:10.1111/j.1440-1789.2011.01274.x © 2011 Japanese Society of Neuropathology