Influence of ApoE on LRP1 Function and Amyloid Transport Across the Blood-Brain Barrier

Shackleton, Ben (2016). Influence of ApoE on LRP1 Function and Amyloid Transport Across the Blood-Brain Barrier. PhD thesis The Open University.



Alzheimer's disease is a progressive incurable neurological disorder and is the leading cause of dementia in the elderly. Common symptoms include failure of memory, language and mood disturbances confusion and depression. The clinical duration of Alzheimer's disease is approximately 8-10 years postdiagnosis and patients require increasing assistance throughout its progression. The currently available treatments are palliative, focussing on improving cognition and only result in mild improvements in small subsets of patients for a relatively short period of time. It is therefore clear that new approaches are needed if a therapy is to be developed that has the potential to be disease modifying and slows the progression of Alzheimer's disease. One of the main pathological hallmarks of Alzheimer's disease is the accumulation of beta-amyloid (Aβ) peptides in the brain. In particular the soluble Ap species has been linked to neurotoxicity, reductions in long term potentiation, and can induce cognitive deficits in animal models of AD after intracerebral injection. In addition, increased accumulation of Ap in the brain is also associated with the APOE4 allele, which is the strongest genetic factor for developing Alzheimer's disease. APOE exists as three alleles with the two copies of the APOE4 allele conferring a 15-fold increase in the risk of developing AD when compared to APOE3 homozygous individuals. Recently it has been demonstrated that this accumulation occurs as a result of defective clearance mechanisms. One of the main routes of clearance of Aβ is through the blood-brain barrier (BBB) where specialised transporters facilitate its clearance. The Low Density Lipoprotein receptor-related protein (LRP1) plays a prominent role in the BBB clearance of Aβ and its surface expression is at least in part regulated by ectodomain cleavage by a variety of 'sheddases'. In particular, this thesis focuses on the previously identified LRP1 sheddases ADAM10 and MMP9. The shedding of LRP1 produces a soluble LRPl fragment, which is unable to endocytose and subsequently transcytose bound ligands. In this thesis, I examined the role of apoE in the regulation of LRP1 and the transcytosis and clearance of Aβ through the BBB. I demonstrate that the shedding of LRP1 is modulated by the different apoE isoforms and that inhibition of LRP1 sheddases increases the clearance of Aβ through the BBB. MMP9 is the primary candidate as the main driver of this mechanism due to its apoE isoform dependent activity and increased expression in AD. In summary, I identified a novel target for treatment strategies that facilitates the clearance of Aβ though the BBB. This approach may be particularly effect in individuals with the APOE4 allele, who are in desperate need of viable therapeutics to combat AD.

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