Critical Review Cholesterol and Alzheimer’s Disease: A Still Poorly Understood Correlation Roberta Ricciarelli 1 *, Elisa Canepa 1 , Barbara Marengo 1 , Umberto M. Marinari 1 , Giuseppe Poli 2 , Maria A. Pronzato 1 , and Cinzia Domenicotti 1 1 Department of Experimental Medicine, University of Genoa, Genoa, Italy 2 San Luigi Hospital, University of Turin, Turin, Italy Summary A large amount of evidence suggests a pathogenic link between cholesterol homeostasis dysregulation and Alzheimer’s disease (AD). In cell culture systems, the production of amyloid- b (Ab) is modulated by cholesterol, and studies on animal mod- els have consistently demonstrated that hypercholesterolemia is associated with an increased deposition of cerebral Ab peptides. Consequently, a number of epidemiological studies have exam- ined the effects of cholesterol-lowering drugs (i.e., statins) in the prevention and the treatment of AD. However, while retrospec- tive studies suggested a potential benefit of statin therapy, clini- cal trials produced inconsistent results. Here, we summarize the main findings from in vitro and in vivo research where the cor- relation between cholesterol and the neurodegenerative disorder was investigated. Recognition of this correlation could be an im- portant step forward for our understanding of AD pathogenesis and, possibly, for the development of new therapeutic strat- egies. Ó 2012 IUBMB IUBMB Life, 64(12): 931–935, 2012 Keywords Alzheimer’s disease; cholesterol; amyloid precursor pro- tein; amyloid beta; apolipoprotein E; statins. INTRODUCTION Amyloid-b (Ab) is a 39–42 amino acid peptide that takes two prevalent forms in humans, Ab 40 and Ab 42 , although longer and shorter peptides also exist. Ab is the natural product of the cleavage of a much larger protein, the amyloid-b precursor pro- tein (APP) (1), by proteases called b- and c-secretases (2–4). Much attention has been focused on this peptide because muta- tions in the APP and c-secretase genes are associated with early onset familial forms of Alzheimer’s disease (AD) and are known to cause cerebral Ab accumulation. However, while these genetic mutations are responsible for the accumulation of Ab in familial AD, the causative factors for Ab load in sporadic forms of AD are still not known. This leads to the possibility that, in the absence of genetic mutations, the identification of risk factors and mechanisms by which these factors contribute to the accumulation of Ab may help in preventing the onset of this devastating disorder. Hypercholesterolemia is such a factor and has been shown by epidemiological and laboratory studies to increase the production of Ab. However, the molecular events by which cholesterol causes Ab accumulation and the real contribution of this steroid to the pathogenesis of AD are still poorly understood. In this review, we summarize the main findings from cell culture, animal model, observational, and clinical studies where the correlation between cholesterol and the neurodegenerative disorder was investigated. CELLULAR CHOLESTEROL AND AMYLOIDOGENESIS Because of the low permeability of the blood-brain barrier to peripheral cholesterol, most of the cholesterol present in the brain derives from de novo synthesis in the central nervous sys- tem (5). Mature neurons are thought to reduce the cholesterol production and rely on glial cells, mainly astrocytes, for their cholesterol supply (6–8). The astrocytic compartment meets neuronal cholesterol demands by secreting cholesterol–apolipo- protein E (apoE) complexes, a mechanism that may involve the activation of the ATP-binding cassette transporter A1 (ABCA1) (9). Moreover, increased levels of ABCA1 were found to lower Ab production in neuronal cultured cells (10), whereas the dele- tion of ABCA1 gene in AD mouse models was associated with greater Ab deposits (11, 12), supporting the idea that cellular Address correspondence to: Roberta Ricciarelli, Department of Ex- perimental Medicine, Section of General Pathology, Via L.B. Alberti, 2, 16132 Genoa, Italy. Tel: +39 010 3538831. Fax: +39 010 3538836. E-mail: ricciarelli@medicina.unige.it Received 9 August 2012; accepted 30 August 2012 ISSN 1521-6543 print/ISSN 1521-6551 online DOI: 10.1002/iub.1091 IUBMB Life, 64(12): 931–935, December 2012