Histochem Cell Biol (2009) 131:661–666 DOI 10.1007/s00418-009-0567-3 123 ORIGINAL PAPER Three-dimensional colocalization analysis of plasma-derived apolipoprotein B with amyloid plaques in APP/PS1 transgenic mice Ryusuke Takechi · Susan Galloway · Menuka Pallebage-Gamarallage · Cheryl Wellington · Russell Johnsen · John Charles Mamo Accepted: 29 January 2009 / Published online: 19 February 2009  Springer-Verlag 2009 Abstract Parenchymal accumulation of amyloid-beta (A) is a hallmark pathological feature of Alzheimer’s dis- ease. An emerging hypothesis is that blood-to-brain deliv- ery of A may increase with compromised blood–brain barrier integrity. In plasma, substantial A is associated with triglyceride-rich lipoproteins (TRLs) secreted by the liver and intestine. Utilizing apolipoprotein B as an exclu- sive marker of hepatic and intestinal TRLs, here we show utilizing an highly sensitive 3-dimensional immuno- microscopy imaging technique, that in APP/PS1 amyloid transgenic mice, concomitant with substantially increased plasma A, there is a signiWcant colocalization of apolipo- protein B with cerebral amyloid plaque. The Wndings are consistent with the possibility that circulating lipoprotein- A contributes to cerebral amyloidosis. Keywords 3-Dimensional colocalization microscopy · Alzheimer’s disease · Amyloid-beta · Apolipoprotein B · Blood–brain barrier Introduction A hallmark neuropathological marker of Alzheimer’s dis- ease (AD) is amyloid-beta (A) deposition in the cerebro- vasculature and brain parenchyma. Why A accumulates in AD is uncertain, although there is little evidence for increased cerebral A production in sporadic, late-onset AD. Rather, diminished clearance of A via the blood– brain barrier (BBB) or choroid plexus may occur with aging (Deane et al. 2005; Crossgrove et al. 2005). There is also emerging evidence of blood-to-brain delivery of A (Mackic et al. 2002), a process that may be exaggerated as a consequence of BBB dysfunction. The cerebrovasculature in subjects with AD shows path- ological alterations including vascular endothelial and smooth muscle cell proliferation (Ellis et al. 1996). Blood derived proteins have been detected in brain parenchyma of AD subjects (Wisniewski et al. 1997) and inXammatory sequealae are reported (Cullen 1997), observations that are consistent with the breakdown of the BBB. In blood, signiWcant A is associated the triglyceride- rich lipoproteins (TRLs) (Mamo et al. 2008) consistent with the Wndings by Koudinov and Koudinova (1997), who found that hepatocytes secrete A exclusively as a lipopro- tein complex. In recent studies, we reported that the absorp- tive epithelial cells of the small intestine (enterocytes) have substantial abundance of A, secreted into blood associated with dietary induced lipoproteins (chylomicrons) (Galloway et al. 2007). Enterocoytic A levels were substantially increased by the ingestion of a high-fat diet but completely abolished by fasting, suggesting that the secretion of lipo- protein-A from the small intestine and liver is regulated by dietary lipids. This Wnding may help explain the mecha- nisms underlying epidemiological studies and animal feed- ing studies that demonstrate an association between the R. Takechi · S. Galloway · M. Pallebage-Gamarallage · J. C. Mamo (&) Australian Technology Network, Centre for Metabolic Fitness, School of Public Health, Curtin Health Innovative Research Institute, Curtin University of Technology, GPO Box U1987, Building 400, Bentley Campus, Perth, WA 6845, Australia e-mail: J.Mamo@Curtin.edu.au C. Wellington Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada R. Johnsen QEII Medical Centre, The Australian Neuromuscular Research Institute, Verdun St, Nedlands, Perth, WA 6009, Australia