title: Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of Alzheimer's disease.
abstract: Parkinson's disease and Alzheimer's disease (AD) are recognized to coexist on a spectrum of neurodegeneration, and it has been proposed that molecular interactions among pathogenic proteins are a basis for the overlap between these two diseases. We instead hypothesized that degeneration of the nigrostriatal dopaminergic system enhances the clinical penetrance of early-stage AD. To determine the effect of striatal dopamine (DA) on the pathological effects in an experimental model of AD, APPSWE /PS1ΔE9 mice received striatal injections of the neurotoxin 6-hydroxydopamine (6OHDA). Animals were tested in a Barnes maze protocol and in a water T-maze protocol at different ages to determine the onset of cognitive impairment. APPSWE /PS1ΔE9 mice that received 6OHDA injections showed significant impairment in Barnes maze performance at an earlier age than controls. Additionally, at 12 months of age, APPswe /PS1ΔE9 + 6OHDA mice demonstrated worse behavioral flexibility than other groups in a task-switch phase of the water T-maze. To determine the neuroprotective effects of dopaminergic neurotransmission against amyloid-β42 (Aβ42 ) toxicity, neuronal branch order and dendrite length were quantified in primary medium spiny neuron (MSN) cultures pretreated with increasing doses of the D1 and D2 receptor agonists before being exposed to oligomerized Aβ42 . Although there were no differences in Aβ peptide levels or plaque burden among the groups, in murine MSN culture dopaminergic agonists prevented a toxic response to Aβ42. Depletion of DA in the striatum exacerbated the cognitive impairment seen in a mouse model of early-stage AD; this may be due to a protective effect of dopaminergic innervation against Aβ striatal neurotoxicity.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Melief
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Nikolas L
authors.initials: NL
authors.lastname: Jorstad
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Emily
authors.initials: E
authors.lastname: Sherfield
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Nadia
authors.initials: N
authors.lastname: Postupna
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Angela
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Martin
authors.initials: M
authors.lastname: Darvas
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity; D019683:Penetrance; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D018663:Adrenergic Agents; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016627:Oxidopamine; D004298:Dopamine
keywords: 6OHDA; Alzheimer's disease; Parkinson's disease; amyloid; cognitive impairment
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