title: Exploring the role of sortilin related receptor 1 in glioblastoma
Creators: name: Jones, Lydia
Publisher: name: University of Central Lancashire
Year: 2025

description: An inverse comorbidity exists between neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease and various cancers. Likely due to occupying opposite ends of the same spectrum; neurodegeneration causing premature cell death and cancer driving uncontrolled cell proliferation. Alzheimer’s disease offers greatest protection against lung cancer but, surprisingly, the impact Alzheimer’s disease may have on brain cancers has not been fully investigated. This thesis will explore the role of the Alzheimer’s disease risk factor protein sortilin related receptor 1 (SorL1) in glioblastoma, the gravest and most common primary brain tumour. SorL1 binds to the amyloid precursor protein to regulate trafficking to the early and late endosomes for cleavage into amyloid beta (A) peptides. In Alzheimer’s disease, SorL1 expression is reduced, increasing A secretion and contributing to the characteristic extracellular amyloid plaques. SorL1 has previously been implicated in peripheral cancers including breast and leukaemia but has never been investigated in glioblastoma. This thesis explores the expression and function of SorL1 in glioblastoma and downstream effects on A40 (most abundant species of A) and A42 (the more aggregate prone species commonly found in Alzheimer’s disease).

Expression of SorL1 in immortalised cell lines (U87MG, 1321N1 and SVGp12) and primary cells (patient derived (PD) 301, PD304 and normal human astrocytes (NHA)), and subsequent expression of A40 and A42 was determined through combinations of immunofluorescence, western blot and ELISA. Secretion of SorL1 into spent medium of PD301, PD304 and NHA cells and in mouse serum from glioblastoma tumour bearing mice was investigated. The contribution SorL1 makes to cell function in glioblastoma was achieved by transiently transfecting PD301 and PD304 cells with siRNA vectors to knock down SorL1. Following confirmation of SorL1 knock down by western blot and immunofluorescence, cell proliferation, viability, migration and impact on amyloid processing was determined.

SorL1 was found to be more highly expressed in glioblastoma cells (U87MG, PD301 and PD304) than control cell counterparts (SVGp12 and NHA) with concomitant reduction in A42 expression in PD301 and PD304 cells compared to NHA cells. Expression of A40 was similar between PD301, PD304 and NHA cells. Furthermore, secretion of SorL1 from PD cells into medium was significantly reduced compared to NHA cells. SorL1 in mouse serum did not change during progression of tumour or between tumour bearing mice or mice following sham surgery. Successful transfection of siRNA against SorL1 in PD301 and PD304 cells knocked down SorL1 by approximately 50%. SorL1 siRNA transfected cells had increased A40 and A42 expression and SorL1 knock down reduced proliferation and migration of glioblastoma cells.

Findings here suggest SorL1 remains functional to drive APP processing away from A42 production in glioblastoma and reducing SorL1 activity may be a potential therapeutic strategy for glioblastoma in the future.