Effects of Reducing Norepinephrine Levels via DSP4 Treatment on Amyloid-β Pathology in Female Rhesus Macaques (Macaca Mulatta)

Article type: Research Article

Authors: Duffy, Kara B.^a | Ray, Balmiki^{b; c} | Lahiri, Debomoy K.^c | Tilmont, Edward M.^d | Tinkler, Gregory P.^e | Herbert, Richard L.^f | Greig, Nigel H.^g | Ingram, Donald K.^h | Ottinger, Mary Ann^{a; i; 1} | Mattison, Julie A.^{d; 1; *}

Affiliations: [a] Animal and Avian Sciences Department, University of Maryland, College Park, MD, USA | [b] Myriad Neuroscience (Assurex Health), Mason, OH, USA (present address) | [c] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Translational Gerontology Branch, National Institute on Aging, NIH Animal Center, Dickerson, MD, USA | [e] Department of Biological Sciences, Kent State University, Kent, OH, USA | [f] Clinical Medicine Branch, National Institute of Allergy and Infectious Disease, NIH, Dickerson, MD, USA | [g] Translational Gerontology Branch, NIA/NIH, Baltimore, MD, USA | [h] Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA | [i] Department of Biology and Biochemistry, University of Houston, Houston, TX, USA (present address)

Correspondence: [*] Correspondence to: Julie A. Mattison, Translational Gerontology Branch, National Institute on Aging, NIH Animal Center, 16701 Elmer School Rd., Bldg 103, Dickerson, MD 20842, USA. Tel.: +1 301 435 7637; E-mail: [email protected].

Note: [1] These authors share senior authorship.

Abstract: The degeneration in the locus coeruleus associated with Alzheimer’s disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer’s disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine β-hydroxylase staining and increased amyloid-β load in the aged group, and the proportion of potentially toxic amyloid-β42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer’s disease, but further refinement is necessary.

Keywords: Alzheimer’s disease, DSP4, locus coeruleus, neurotoxin, nonhuman primate, norepinephrine

DOI: 10.3233/JAD-180487

Journal: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 115-126, 2019