Depression in Alzheimer’s disease: a role for the Locus coeruleus

Sedgwick, Katie 2022. Depression in Alzheimer’s disease: a role for the Locus coeruleus. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Neuropsychiatric symptoms (NPS) are a common yet often overlooked aspect of Alzheimer’s disease (AD) associated with accelerated disease progression and reduced quality of life. Amyloid pathology, both soluble oligomers and insoluble plaques, has been heavily linked to the development of NPS along with locus coeruleus (LC) noradrenergic signalling. A knock-in (KI) mouse model, AppNL-G-F, was used to examine this question through a battery of affective and biochemical tests to examine the link between amyloid, LC and NPS. The final experiment looked at how LC-NA signalling changes could lead to depressive symptoms seen in AD. AppNL-G-F mice expressing Swedish (KM670/671NL), Iberian/Beyreuther (I716F) and arctic (E694G) mutations, were tested at both a young and old time point across both sexes. Reduced anxiety was found across elevated plus maze (EPM) for females only and open field (OF) while no social or cognitive deficits were found compared to wildtype (WT) mice. AppNL-G-F mice had reduced sucrose consumption with normal liking behaviour suggesting no depressive phenotype but rather an apathetic one. Biochemical analysis revealed increased gliosis with altered neurotrophic support. Interestingly, increased gliosis was not accompanied by elevated common cytokine levels but some chemokines were increased (e.g.CCL3 & CCL4). Despite there being no changes to mature brain derived neurotrophic factor (BDNF), there were increased levels of its receptor and precursor, TrkB and proBDNF in the cortex. No LC cell loss was found at either time point. Combined with the behavioural data, this suggests amyloid causes apathy through increased gliosis and the lack of cognitive, anxious and depressive effects could be due to the lack of tauopathy and LC damage. Disrupted noradrenergic signalling relates to depression and was examined in a DSP4, a noradrenergic specific neurotoxin, injected WT mice as well as postmortem human tissue. Only subtle trends for increased depressive behaviour were seen in the mice but no changes in tyrosine hydroxylase, the rate limiting enzyme in noradrenaline production, were seen in depressed and non-depressed AD and non-AD patients. Results remain inconclusive due to confounds but the subtle trends suggest some link between LC and depression. Together, this work suggests amyloid causes apathy and reduced anxiety possibly through increased gliosis but the lack of cognitive, anxious and depressive effects could be down to intact LC iii and normal BDNF levels. Results are discussed around whether amyloid would be a good target for NPS treatments.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Psychology
Date of First Compliant Deposit:	31 May 2023
Last Modified:	31 May 2023 13:56
URI:	https://orca.cardiff.ac.uk/id/eprint/160077

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