SorLA and Amyloid Beta Expression in Glioma

Williams, Morgan Huw (2019) SorLA and Amyloid Beta Expression in Glioma. Masters thesis, University of Central Lancashire.

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Glioma is the collective term for cancerous glial-cell tumours. The most prominent of these cancers is glioblastoma (GB); the most common primary malignant brain tumour and the most aggressive. Treatment options for GB are severely limited, not least because of an incomplete understanding of the molecular mechanisms underlying disease onset and progression.

SorLA is a widespread type 1 transmembrane protein involved as a sorting receptor for an array of ligands in multiple tissues. Most studies into SorLA have focused on its role in the pathological processing of amyloid precursor protein (APP) in Alzheimer’s disease. Reduced SorLA expression increases amyloidogenic APP cleavage to liberate toxic forms of amyloid beta (Aβ). A few recent reports have linked enhanced SorLA expression to various malignancies including leukaemia, lymphoma, pancreatic and bile duct cancers. Ectodomain shedding of soluble SorLA (sSorLA) has been posited as a hypoxia-induced migration inducer, contributing to the malignancy. Indeed, it has been proposed that sSorLA may be a viable biomarker for these diseases.

SorLA’s involvement in glioma has received very little attention. Using a combination of immunofluorescence (IF) imaging of GB cell lines in vitro and immunocytochemistry (IHC) of a mouse xenograft glioma model, this thesis tests the hypothesis that SorLA expression is upregulated in GB, and that Aβ is downregulated.

Analysis of IF confirmed expression of SorLA in GB cell lines and human foetal astrocytes. Differences in expression levels were not significant, likely owing to limitations of the methodology employed.

Standard histochemical analysis confirmed the success of the mouse xenograft model of GB in forming tumours. IHC using antibodies against SorLA in this model revealed staining in both tumour and non-tumour regions. Within the tumour itself, staining was restricted to large extracellular deposits of significantly larger size than in non-tumour regions.

Interestingly, the total SorLA staining was comparatively greater in non-tumour areas, where a more uniform pattern of intracellular staining was seen. Since the antibody employed could not distinguish between transmembrane and soluble forms of SorLA, due to the region of binding being found on both forms of the protein; this might indicate a propensity for sSorLA to be shed extracellularly within the tumour but remain intracellular in normal brain. Given the role of SorLA in Aβ production and the plaque-like structures seen within the tumours, IHC was performed to identify the presence of Aβ in tumour and non-tumour tissues. Aβ immunoreactivity was detected throughout the brain but localised to thread-like structures between cells and large extracellular plaques which resembled the senile plaques seen AD but did not co-localise with SorLA. Unexpectedly, a halo region of Aβ peripheral to the tumour was visible, with staining intensity decreasing with distance from the tumour margin. Whether this expression was an exfiltration of Aβ from the tumour or emanated from the tumour microenvironment was not an aim of this thesis, but would warrant further investigation.

In conclusion, this investigation revealed that SorLA is expressed in astrocytes and in glioma cell lines. Moreover, SorLA was expressed in a mouse glioma xenograft model and formed extracellular plaques within the tumour, most likely comprised of aggregations of sSorLA. This is due to sSorLA lacking the cytosolic tail motif unlike SorLA, which is kept membrane-bound by said motif. The study also found that amyloid beta was also present in tumour tissue in the form of extracellular plaques and in non-tumour tissue immediately peripheral to the tumour. Taken together, these data indicate that SorLA and Aβ may have a role in glioma and warrant further investigation, particularly as literature mentions that a lack of intracellular SorLA increases the presence of Aβ.

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