Broad-Based Nutritional Supplementation in 3xTg Mice Corrects Mitochondrial Function and Indicates Sex-Specificity in Response to Alzheimer's Disease Intervention

Article type: Research Article

Authors: Wolf, Andrew B.^{a; b; i} | Braden, B. Blair^{b; i} | Bimonte-Nelson, Heather^{b; i} | Kusne, Yael^{a; b; i} | Young, Nicole^{a; b; i} | Engler-Chiurazzi, Elizabeth^{b; i} | Garcia, Alexandra N.^{b; i} | Walker, Douglas G.^{c; i} | Moses, Guna S.D.^{c; d; i} | Tran, Hung^{c; i} | LaFerla, Frank^e | Lue, LihFen^{c; i} | Emerson Lombardo, Nancy^{f; g} | Valla, Jon^{a; h; i; *}

Affiliations: [a] Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA | [b] Arizona State University, Tempe, AZ, USA | [c] Banner Sun Health Research Institute, Sun City, AZ, USA | [d] Grand Canyon University, Phoenix, AZ, USA | [e] Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA | [f] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [g] Veterans Administration Medical Center, Bedford, MA, USA | [h] Midwestern University, Glendale, AZ, USA | [i] Arizona Alzheimer's Consortium, Phoenix, AZ, USA

Correspondence: [*] Correspondence to: Jon Valla, Department of Biochemistry, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA. Tel.: +1 623 572 3729; Fax: +1 623 572 3679; E-mail: [email protected].

Abstract: Nutrition has been highlighted as a potential factor in Alzheimer's disease (AD) risk and decline and has been investigated as a therapeutic target. Broad-based combination diet therapies have the potential to simultaneously effect numerous protective and corrective processes, both directly (e.g., neuroprotection) and indirectly (e.g., improved vascular health). Here we administered either normal mouse chow with a broad-based nutritional supplement or mouse chow alone to aged male and female 3xTg mice and wildtype (WT) controls. After approximately 4 months of feeding, mice were given a battery of cognitive tasks and then injected with a radiolabeled glucose analog. Brains were assessed for differences in regional glucose uptake and mitochondrial cytochrome oxidase activity, AD pathology, and inflammatory markers. Supplementation induced behavioral changes in the 3xTg, but not WT, mice, and the mode of these changes was influenced by sex. Subsequent analyses indicated that differential response to supplementation by male and female 3xTg mice highlighted brain regional strategies for the preservation of function. Several regions involved have been shown to mediate responses to steroid hormones, indicating a mechanism for sex-based vulnerability. Thus, these findings may have broad implications for the human response to future therapeutics.

Keywords: Biomarkers, cytochrome-c oxidase (Complex IV), diet therapy, memory, sex, transgenic mice

DOI: 10.3233/JAD-2012-120478

Journal: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 217-232, 2012