Affiliations: [a] Robarts Research Institute, Western University, London, Canada
| [b] Department of Anatomy and Cell Biology, Western University, London, Canada
| [c] Department of Radiology, Stanford University, Stanford, CA, USA
| [d] Department of Medical Biophysics, Western University, London, Canada
Correspondence:
[*]
Correspondence to: John Ronald, PhD, Assistant Professor, Department of Medical Biophysics Scientist, Robarts Research Institute, 1151 Richmond St. N, Rm. 2241A, Western University, London, ON N6A 5B7, Canada. Tel.: +1 519 931 5777/Ext. 24391; Fax: +1 519 931 5789; E-mail: [email protected].
Abstract: Microglial activation and oxidative stress have been linked to the formation of amyloid plaques found in Alzheimer’s disease (AD). Epidemiologic and experimental evidence also suggests that cholesterol (CH) contributes to the pathogenesis of AD, particularly the formation of amyloid plaques. We have previously described the development of amyloid-β (Aβ) plaques in New Zealand white rabbits maintained on a 0.125%–0.25% w/w CH diet for extended periods of time (28 months). Here we further characterize this model with combined immunofluorescence and immunohistochemical staining to evaluate markers of immune cell activation. Five out of eight CH-fed rabbits, but not control rabbits, developed extracellular Aβ plaques in both the hippocampus and cortex. Significantly (p < 0.05) higher CD11b microglial staining was found in the hippocampus, temporal cortex, and frontal cortex of CH-fed versus control rabbits. In the temporal cortex and parietal cortex, active CD-11b- and ferritin-positive microglia were found in close proximity to Aβ plaques. Classification and quantification of activated microglia in the temporal cortex showed that 68±12.9%, 25±7.3%, and 7±2.7% of all microglia had a primed, reactive, and amoeboid phenotype, respectively. Activated microglia also expressed myeloperoxidase which was co-localized to amyloid deposits. Our findings in this dietary-based model lend further support of a role of activated microglia and oxidative stress during the development of AD and strengthens the links between hypercholesterolemia, inflammatory status, and AD.
Keywords: Alzheimer’s disease, amyloid-β plaque, cholesterol, microglia, myeloperoxidase, rabbit model
