Journal of Alzheimer’s Disease 31 (2012) 813–826 DOI 10.3233/JAD-2012-120298 IOS Press 813 Cholesterol and Synaptic Compensatory Mechanisms in Alzheimer’s Disease Mice Brain During Aging Diane Jansen a , Carola I.F. Janssen a , Tim Vanmierlo b , Pieter J. Dederen a , Daan van Rooij a , Bastian Zinnhardt a , Cindy L.M. Nobelen a , Anna-Lena Janssen a , Anne Hafkemeijer a , Martina P.C. Mutsaers a , Anne M.C.M. Doed´ ee a , Almar A.M. Kuipers c , Laus M. Broersen c , Monique Mulder d and Amanda J. Kiliaan a,∗ a Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b Department of Neuroscience, Maastricht University, Maastricht, The Netherlands c Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition, Wageningen, The Netherlands d Department of Internal Medicine, Div. Pharmacology, Vascular and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands Handling Associate Editor: Gary Arendash Accepted 14 May 2012 Abstract. Research into the development of Alzheimer’s disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake and the cholesterol-lowering liver X receptor-agonist T0901317 on capillary density, amyloid- deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) APPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. Our results show increased number of presynaptic boutons in 15-month-old APP-PS1 mice compared to age-matched wild-type animals, but no difference at 8 months of age. High cholesterol intake accelerated this response by increasing the amount of presynaptic boutons at 8 and 15 months of age, while T0901317 intake decreased the amount of presynaptic boutons in 15-month-old APP-PS1 mice. These findings suggest a synaptic compensatory response to maintain connectivity during aging. We hypothesize that high cholesterol intake may cause impaired cerebral blood flow inducing ischemia, fortifying the above mentioned hypothesis of a compensatory mechanism. Contrarily, cholesterol-lowering agents may positively influence cerebral circulation, thereby diminishing aggravation of AD-like pathology. Keywords: Aging, Alzheimer’s disease, amyloid-, cholesterol, glucose transporter type-1, hippocampus, liver X receptor, synapse, synaptophysin, T0901317, transgenic mice ∗ Correspondence to: Amanda J. Kiliaan, Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, PO BOX 9101, 6500HB Nijmegen, The Netherlands. Tel.: +31 24 3614378; Fax: +31 243613789; E-mail: A.Kiliaan@anat.umcn.nl. INTRODUCTION Alzheimer’s disease (AD) is a progressive neu- rodegenerative disorder and the most common cause of dementia in the elderly. Clinically, the disease is marked by early gradual cognitive impairment. ISSN 1387-2877/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved