DEVELOPMENT OF ALZHEIMER'S-LIKE PATHOLOGY IN NON-HUMAN PRIMATES WITH REDUCED LEVELS OF NOREPINEPHRINE
Duffy, Kara Beth
Ottinger, Mary Ann
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Synthesis of the norepinephrine distributed to sub-cortical and cortical brain regions occurs in the locus coeruleus. Impaired function results in reduced availability of norepinephrine. Locus coeruleus degeneration is a well-documented feature of Alzheimer's disease; however, the role of catecholaminergic dysfunction remains unclear. Deregulation of this system may accelerate the development and progression of Alzheimer's disease, particularly in patients without familial gene mutations. Currently no animal model exists for idiopathic Alzheimer's disease, which accounts for the majority of human cases. To ascertain the role of the noradrenergic system on the development of amyloid pathology and amyloid-β synthesis pathway, female non-human primates received injection of 40 mg/kg of the neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) or vehicle and subsequent injections three and six months later (10 mg/kg DSP-4). At nine months, brain samples were processed for catecholamines. Distribution of amyloid identified by 6E10 and localization of dopamine β-hydroxylase to visualize locus coeruleus neurons was examined using immunostaining in tissue sections. Brain levels of amyloid precursor protein, soluble amyloid-β peptides (1-40 and 1-42) along with β-site APP cleaving enzyme-1 were also measured. Results showed norepinephrine depletion in the locus coeruleus following DSP4 injection. Reduction of dopamine β-hydroxylase was detected in aged rhesus monkeys after DSP4. Distribution of amyloid identified by 6E10 was exacerbated in squirrel monkeys following DSP4 and elevated in aged rhesus monkeys after DSP4; additionally DSP4 increased the amyloid-β42 to amyloid-β40 ratio in aged rhesus monkeys. Species specific alterations in amyloid precursor protein and β-site amyloid precursor protein cleaving enzyme-1 were observed and rhesus monkeys were more sensitive to effects of DSP4. These data provide evidence for a potential mechanism important in Alzheimer's disease pathology development and indicate that decreased norepinephrine contributed to an increase in soluble amyloid isoforms and increased accumulation in neocortex in non-human primates. Altered amyloid precursor protein processing contributes to increased amyloid pathology in the absence of chronic neuroinflammation. Non-human primates are an ideal candidate for an animal model because amyloid pathology and neurodegenerative disease characteristics occur naturally later in life, similar to humans.