The role of the Locus Coeruleus in depression in Alzheimer’s disease

Abstract

AbstractBackgroundDepression, one of many common neuropsychiatric symptoms (NPS) seen in Alzheimer’s disease (AD), frequently predisposes the onset of cognitive deficits. NPS are often reported to cause the most suffering in patients and their loved ones so understanding their cause could lead to treatments that afford a better quality of life. The Locus coeruleus (LC) has strong links to depression and, being one of the first areas to show AD pathology, could be integral to understanding this NPS‐AD link. Alongside a natural LC neuron loss with age, AD causes its neurodegeneration reducing the LC’s neuroprotective capabilities and control of inflammatory pathways. Examination of the LC, inflammation and depressive phenotype could offer insights into future treatments.MethodBehavioural testing was done using a novel, knock‐in mouse model, AppNL‐G‐F , to assess depressive phenotype at an early and old time point. This included tests for anxiety (open field, elevated plus maze), social deficits (social preference test) and anhedonia (lick cluster analysis) all common NPS symptoms. Brains extracted from these animals were used to stain for LC neurons, plaques and microglia as well as assess astrocytes and inflammatory markers using western blotting technique.ResultAn anxiolytic phenotype was prominent but no social deficits or anhedonia suggesting a lack of depressive phenotype. There was also no loss of LC neurons with age or genotype. Western blotting revealed a large increase in astrocytes within the AppNL‐G‐F but no differences in inflammatory markers.ConclusionOverall, without the loss of LC neurons, it is difficult to draw firm conclusions on its role in NPS onset. Hence, the AppNL‐G‐F mice are insufficient at modelling affective deficits seen in human AD due to the lack of neurodegeneration of the LC. It may be concluded that, as this is a model of amyloid beta pathology, that plaques and inflammation play a minimal role in NPS without LC loss. Future testing could lesion the LC to better understand its role.