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Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions.In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aβ status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts.Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

Background: We and others have reported that glatiramer acetate promotes innate phagocytosis. Methods: In this study, we investigated the interaction between glatiramer acetate and amyloid-β (Aβ) by using circular dichroism and microscale thermophoresis. Glatiramer acetate was delivered intracerebroventricularly to 22-month-old APP/PS1 mice by using mini-osmotic pumps. Mice underwent behavioural testing for two consecutive weeks after three-weeks treatment. Five weeks after implantation, animals were sacrificed and brain samples were collected for electrophysiology, immunochemistry and histopathology studies. Intracerebroventricular delivery of glatiramer acetate to sheep was also examined. Results: Glatiramer acetate binds to amyloid-β within high affinity and antagonize its toxicity. Glatiramer acetate treatment significantly improved cognitive function, restored long-term potentiation, reduced soluble amyloid-β and amyloid-β plaques in aged APP/PS1 mice, and promoted energy metabolism in sheep. Conclusions: Our results suggest a novel treatment strategy that targets both innate phagocytosis and amyloid-β, which may prove useful for treatment of all stages of Alzheimer’s disease.

We have shown deficits in monocyte phagocytosis from patients with age-related macular degeneration (AMD). Cell membrane fluidity is known to affect phagocytic capacity and leucocyte functionality more generally. Therefore, we examined membrane fluidity of peripheral blood leucocytes in human patients with AMD and in the P2X7 null mouse model of AMD using flow cytometry with a fluorescent probe for fluidity, TMA-DPH. The results showed that membrane fluidity was decreased in all leucocyte types of late AMD relative to healthy controls (HC) including monocytes, neutrophils and lymphocytes but this was not apparent in earlier stages of AMD. Further analysis of factors contributing to membrane fluidity indicated that pre-treatment of monocytes and lymphocytes with ATP greatly increased membrane fluidity in humans and mice. Evidence from P2X7 null mice and P2X7 antagonists confirmed that these ATP-driven increases in membrane fluidity were mediated by P2X7 but were not associated with the classic P2X7 functions of pore formation or phagocytosis. Analysis of P2X7 expression indicated that receptor levels were elevated in classic monocytes of late AMD patients, further suggesting the P2X7 may contribute to altered plasma membrane properties. Our findings identified a novel biological function of P2X7 in modulating membrane fluidity of leucocytes and demonstrated reduced membrane fluidity in cellular changes associated with the late stage of AMD.