Genetic deletion of Alox15 is associated with spatial and anxiety phenotypes related to normal ageing.

Gketsopoulou, Anastasia 2022. Genetic deletion of Alox15 is associated with spatial and anxiety phenotypes related to normal ageing. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Lipoxygenases are a family of enzymes that generate bioactive inflammatory lipid mediators. Among them, the Alox15 gene product (15-LOX, 12/15-LOX) has been detected in neurons and glial cells in mice. There is an emerging interest in its potential role in neurodegenerative disease; however, the biological role of this enzyme in the healthy brain has not yet been characterised. This thesis investigates the impact of 12/15-LOX deletion on mouse cognitive function and lipid profiling. Two independent groups of young to middle-aged and old wild type (WT) or Alox15-/- mice were studied. A range of behavioural tests, including a novel object recognition task, object location task and elevated plus maze, were used to assess the effects of deletion on cognition and emotional reactivity compared with similarly aged control WT mice. At 10 months of age, both male and female Alox15-/- mice displayed spatial memory deficits that may be linked to hippocampal impairments. In contrast, knock-out mice showed normal novel object recognition memory. Also, Alox15-/- mice manifested increased anxiety-like behaviour compared to controls. Their increased anxiety phenotype was connected to alterations in the expression levels of various protein markers, including parvalbumin, GABAergic, corticotrophin-releasing factor, and serotonergic receptors. Separately, liquid chromatography with tandem mass spectrometry was used to quantify oxylipins and enzymatically oxidised phospholipids (oxPL) generated via the 12/15- LOX during healthy brain ageing across various brain regions in both groups of mice. Lipidomic analysis of brain regions extracted and revealed elevated levels of selected oxylipins (5-HETE, prostaglandins) but reduced levels of the Alox15 product, 12-HETE. In eoxPL analysis, the deficiency of Alox15 did not change the levels of PE 18:0a_12-HETE between genotypes. Taken together, these results suggest a role for 12/15-LOX in regulating normal brain function, and further work is required to determine the biological basis of the anxiety phenotype in mice lacking this enzyme.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	19 May 2023
Last Modified:	19 May 2024 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/159685

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