Investigation of the role of BACE1 in adipocyte and immune cell function

Metabolic disorders, including obesity and type 2 diabetes (T2D), place a huge health and economic burden on society with the National Health Service (NHS) becoming increasingly overwhelmed. Moreover, metabolic disorders often manifest with numerous co-morbidities that include cardiovascular disease (CVD), various cancers and Alzheimer’s disease (AD), exacerbating the problem. Therefore research into metabolic dysregulation and its associated conditions is vital for the future treatment of these disorders and so to relieve the social and financial burdens. <br/><br/>AD commonly co-manifests alongside metabolic diseases and this neurodegenerative condition is hugely prevalent in the aging population of today. One of the major pathologies, which many believe to be causative, associated with AD is amyloid plaque formation. Amyloid plaques occur as an aggregated form of amyloid peptides whose formation is dependent upon cleavage by an aspartyl protease named BACE1 (β-site amyloid precursor protein cleaving enzyme 1). This enzyme is the rate-limiting enzyme involved in the cleavage of amyloid precursor protein (APP) which, followed by γ-secretase cleavage, results in amyloid (or Aβ) peptide formation leading to amyloid plaques. <br/><br/>BACE1 has also recently been implicated in metabolism with the discovery that BACE1 KO mice are protected against diet-induced obesity (DIO) and its associated diabetes. These findings were supported by use of BACE1 inhibitors in obese mice which mimicked the knock-out studies and subsequently were found to modulate energy homeostasis both in vivo and in vitro. In addition to an improved metabolic phenotype BACE1 KO mice exhibited protection against the chronic inflammation commonly linked to obesity. This was shown by a reduction in immune cell infiltration, in particular macrophages, in the white adipose tissue (WAT) and liver accompanied by reduced levels of pro-inflammatory, and increased levels of anti-inflammatory, cytokines within the WAT. This led to the hypothesis that removal of BACE1 from either the myeloid cells or adipocytes may mediate the advantageous phenotype of the global BACE1 KO mouse and once the key cell type was identified allow investigation into the mechanism underlying this phenotype. <br/><br/>This project, alongside a parallel study, aimed to address this hypothesis. Results gathered from this study revealed that BACE1 removal from myeloid cells did not significantly alter the metabolic phenotype of these mice when compared to their littermates. Furthermore, the chronic inflammatory status of these mice also remained relatively unaltered. In contrast, results generated by Dr. David Allsop revealed that adipocyte BACE1 played a prevalent role in regulating energy homeostasis and subsequently this was investigated further in the latter stages of this project. Results reveal that the effects of reducing adipocyte BACE1 in improving the metabolic phenotype is likely to be mediated through increases in energy expenditure and thermogenesis.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2019

Author dc:creator

• Cavellini, Daniella L.

Advisors dc:contributor.advisor

• Ashford, Michael
• Arthur, John

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/db34cfce-23e5-4b4d-ab56-ab2b724b55de

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/db34cfce-23e5-4b4d-ab56-ab2b724b55de