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Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of A lzheimer's disease
Author(s) -
Melief Erica J.,
Cudaback Eiron,
Jorstad Nikolas L.,
Sherfield Emily,
Postupdia,
Wilson Angela,
Darvas Martin,
Montine Kathleen S.,
Keene C. Dirk,
Montine Thomas J.
Publication year - 2015
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23592
Subject(s) - dopaminergic , dopamine , neuroprotection , neurodegeneration , neuroscience , striatum , neurotoxin , morris water navigation task , psychology , genetically modified mouse , medicine , pharmacology , endocrinology , biology , transgene , disease , cognition , biochemistry , gene
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, APP SWE /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. APP SWE /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, APP swe /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‐β 42 (Aβ 42 ) toxicity, neuronal branch order and dendrite length were quantified in primary medium spiny neuron (MSN) cultures pretreated with increasing doses of the D 1 and D 2 receptor agonists before being exposed to oligomerized Aβ 42 . 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 Aβ 42. 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. © 2015 Wiley Periodicals, Inc.