Extensive loss of noradrenaline-containing neurons and fibers is a nearly invariant feature of Alzheimer’s Disease (AD). However, the exact noradrenergic contribution to cognitive and histo- pathological changes in AD is still unclear. Here, this issue was addressed following selective lesioning and intrahippocampal implantation of embryonic noradrenergic progenitors in developing rats. Starting from about 3 months and up to 12 months post-surgery, animals underwent behav- ioral tests to evaluate sensory-motor, as well as spatial learning and memory, followed by post- mortem morphometric analyses. At 9 months, Control, Lesioned and Lesion1Transplant animals exhibited equally efficient sensory-motor and reference memory performance. Interestingly, work- ing memory abilities were seen severely impaired in Lesion-only rats and fully recovered in Transplanted rats, and appeared partly lost again 2 months after ablation of the implanted neuro- blasts. Morphological analyses confirmed the almost total lesion-induced noradrenergic neuronal and terminal fiber loss, the near-normal reinnervation of the hippocampus promoted by the trans- plants, and its complete removal by the second lesion. Notably, the noradrenergic-rich transplants normalized also the nuclear expression of the transactive response DNA-binding protein 43 (TDP- 43) in various hippocampal subregions, whose cytoplasmic (i.e., pathological) occurrence appeared dramatically increased as a result of the lesions. Thus, integrity of ascending noradrenergic inputs to the hippocampus may be required for the regulation of specific aspects of learning and memory and to prevent TDP-43 tissue pathology.

Essential role of hippocampal noradrenaline in the regulation of spatial working memory and TDP-43 tissue pathology

Rosario Gulino;LEANZA, Giampiero
2018-01-01

Abstract

Extensive loss of noradrenaline-containing neurons and fibers is a nearly invariant feature of Alzheimer’s Disease (AD). However, the exact noradrenergic contribution to cognitive and histo- pathological changes in AD is still unclear. Here, this issue was addressed following selective lesioning and intrahippocampal implantation of embryonic noradrenergic progenitors in developing rats. Starting from about 3 months and up to 12 months post-surgery, animals underwent behav- ioral tests to evaluate sensory-motor, as well as spatial learning and memory, followed by post- mortem morphometric analyses. At 9 months, Control, Lesioned and Lesion1Transplant animals exhibited equally efficient sensory-motor and reference memory performance. Interestingly, work- ing memory abilities were seen severely impaired in Lesion-only rats and fully recovered in Transplanted rats, and appeared partly lost again 2 months after ablation of the implanted neuro- blasts. Morphological analyses confirmed the almost total lesion-induced noradrenergic neuronal and terminal fiber loss, the near-normal reinnervation of the hippocampus promoted by the trans- plants, and its complete removal by the second lesion. Notably, the noradrenergic-rich transplants normalized also the nuclear expression of the transactive response DNA-binding protein 43 (TDP- 43) in various hippocampal subregions, whose cytoplasmic (i.e., pathological) occurrence appeared dramatically increased as a result of the lesions. Thus, integrity of ascending noradrenergic inputs to the hippocampus may be required for the regulation of specific aspects of learning and memory and to prevent TDP-43 tissue pathology.
2018
Alzheimer’s disease, cell transplantation, immunolesion, noradrenaline, rat, working memory, TDP- 43, RRID: AB_2245740, RRID: AB_615042
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/323668
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