In the past, manipulation of the cholinergic system was seen as the most likely therapeutic 78 for neurodegeneration-based cognitive decline in Alzheimer’s disease (AD) (Whitehouse 79 et al., 1982). However, targeting the noradrenergic system also seems a promissing 80 strategy, since more recent studies revealed that in post-mortem tissue from patients 81 82 with AD and other neurodegenerative disorders there is a robust correlation between 83 cognitive decline and loss of neurons from the Locus coeruleus (LC), a system with 84 diffuse noradrenaline (NA) innervation in the central nervous system (CNS). Therefore, 85 the hypothesis has been considered that increasing NA signaling in the CNS will prevent, 86 87 or at least halt the progression of neurodegeneration and cognitive decline. A hallmark 88 of the age- and neurodegeneration-related cognitive decline is reduced neurogenesis. 89 We here discuss noradrenergic dysfunction in AD-related cognitive decline in humans 90 and its potential involvement in AD pathology and disease progression. We also focus 91 on animal models to allow the validation of the noradrenergic hypothesis of AD, including 92 those based upon the immunotoxin-mediated ablation of LC based on saporin, a protein 93 94 synthesis interfering agent, which offers selective and graded demise of LC neurons, 95 Finally, we address how astrocytes, an abundant and functionally heterogeneous cell type 96 of neuroglia maintaining homeostasis, may participate in the regulation of neurogenesis, 97 a new strategy for preventing LC neuron loss.

Noradrenergic hypothesis linking neurodegeneration-based cognitive decline and astroglia

Giampiero Leanza;Rosario Gulino;
2018

Abstract

In the past, manipulation of the cholinergic system was seen as the most likely therapeutic 78 for neurodegeneration-based cognitive decline in Alzheimer’s disease (AD) (Whitehouse 79 et al., 1982). However, targeting the noradrenergic system also seems a promissing 80 strategy, since more recent studies revealed that in post-mortem tissue from patients 81 82 with AD and other neurodegenerative disorders there is a robust correlation between 83 cognitive decline and loss of neurons from the Locus coeruleus (LC), a system with 84 diffuse noradrenaline (NA) innervation in the central nervous system (CNS). Therefore, 85 the hypothesis has been considered that increasing NA signaling in the CNS will prevent, 86 87 or at least halt the progression of neurodegeneration and cognitive decline. A hallmark 88 of the age- and neurodegeneration-related cognitive decline is reduced neurogenesis. 89 We here discuss noradrenergic dysfunction in AD-related cognitive decline in humans 90 and its potential involvement in AD pathology and disease progression. We also focus 91 on animal models to allow the validation of the noradrenergic hypothesis of AD, including 92 those based upon the immunotoxin-mediated ablation of LC based on saporin, a protein 93 94 synthesis interfering agent, which offers selective and graded demise of LC neurons, 95 Finally, we address how astrocytes, an abundant and functionally heterogeneous cell type 96 of neuroglia maintaining homeostasis, may participate in the regulation of neurogenesis, 97 a new strategy for preventing LC neuron loss.
noradrenaline (norepinephrine), cognitive decline, Alzheimer’s disease, neurodegeneration, 100 neurogenesis, astroglia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/355419
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