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

Kara B. Duffy, Balmiki Ray, Debomoy K. Lahiri, Edward M. Tilmont, Gregory P. Tinkler, Richard L. Herbert, Nigel H. Greig, Donald K. Ingram, Mary Ann Ottinger, Julie A. Mattison

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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-β 42 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.

Original languageEnglish (US)
Pages (from-to)115-126
Number of pages12
JournalJournal of Alzheimer's Disease
Volume68
Issue number1
DOIs
StatePublished - Jan 1 2019

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Keywords

  • Alzheimer's disease
  • DSP4
  • locus coeruleus
  • neurotoxin
  • nonhuman primate
  • norepinephrine

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Duffy, K. B., Ray, B., Lahiri, D. K., Tilmont, E. M., Tinkler, G. P., Herbert, R. L., Greig, N. H., Ingram, D. K., Ottinger, M. A., & Mattison, J. A. (2019). Effects of Reducing Norepinephrine Levels via DSP4 Treatment on Amyloid-β Pathology in Female Rhesus Macaques (Macaca Mulatta). Journal of Alzheimer's Disease, 68(1), 115-126. https://doi.org/10.3233/JAD-180487