Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins

Simple Summary Noradrenaline is a crucial neurotransmitter produced by a group of neurons in the locus coeruleus and plays a significant role in regulating various physiological processes, including attention, arousal and stress responses. Alzheimer's disease is a progressive and devastating neurodegenerative disorder that affects millions of people worldwide. It is characterized by the accumulation in the brain of abnormal protein aggregates, such as amyloid-beta, tau and TDP-43, leading to the deterioration of neurons and cognitive decline. Studies have shown that the noradrenergic system is severely affected by Alzheimer's disease. This depletion of noradrenaline levels has been associated with the cognitive decline and behavioral symptoms observed in Alzheimer's patients. In this study, we showed that administering increasing doses of a selective noradrenergic immunotoxin caused dose-dependent working memory impairments and accumulation of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217 in the cortex and hippocampus of developing rats. These findings suggest that boosting noradrenergic activity may have beneficial effects on cognitive functions and slow down disease progression. However, further research is needed to fully comprehend the complex relationship between noradrenaline, cognitive function and the aberrant accumulation of proteins in Alzheimer's disease and to develop effective treatments based on these findings.Abstract Noradrenaline (NA) depletion occurs in Alzheimer's disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential.