The Role of Innate Phagocytosis in the Pathogenesis and Treatment of Alzheimer’s Disease (for PhD only)
Emerging genetic evidence suggests that impaired removal of aggregated or fibrillar Aβ-peptides due to defects in innate phagocytosis is a major contributor to the risk of sporadic Alzheimer’s disease (AD).
We found that both proinflammation and innate phagocytosis can be mediated by the P2X7 receptor in the presence or absence of its ligand extracellular ATP. In a blind pilot study we measured the phagocytic ability of fresh peripheral monocyte subsets from over 90 patients and controls recruited via the Australian Imaging Biomarker and Lifestyle Study of Aging (AIBL). Cells treated with ATP showed decreased phagocytic ability while Copaxone (CPX, also known as glatiramer acetate, a peptide polymer drug for multiple sclerosis) promoted innate phagocytosis. Significant differences of ATP and CPX altered phagocytosis were found between cognitively normal older controls and patients with mild cognitive impairment (MCI) or AD, and both were correlated with amyloid burden as assayed by Aβ amyloid-PET imaging (Gu et al, Acta Neuropathologica 2016). In this project, the candidate will further investigate the underlining biological mechanisms of these correlations through cell ageing, membrane fluidity, innate phagocytosis and inflammation. A combination treatment targeting both innate phagocytosis and inflammation will be developed in an animal model of AD and a small-scale Phase IIa pilot clinic trial for prodromal or mild/moderate AD patients, based on our novel findings. The safety and tolerance for the treatment combination (CPX which promotes innate phagocytosis and AZD9056 which inhibits P2X7 mediated proinflammation) and its therapeutic effect will be assessed during this trial. Outcome measures for Proof of Concept and Proof of Mechanism include reversal of the peripheral monocyte phagocytic deficits and changes in brain microglial activation as assessed by PET-TSPO imaging. This study will lead to better understanding of the pathogenesis of AD and a novel treatment strategy for AD.
Techniques involved include flow cytometry, microsurgery, cell culture, animal handling, fluorescent microscopy and biochemistry.
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