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 /PS1?E9 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 /PS1?E9 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 /PS1?E9?+?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-?42 (A?42 ) 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 A?42 . Although there were no differences in A? peptide levels or plaque burden among the groups, in murine MSN culture dopaminergic agonists prevented a toxic response to A?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 A? striatal neurotoxicity.

SUBMITTER: Melief EJ 

PROVIDER: S-EPMC4504797 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature