Alzheimer disease (AD) is the most frequent form of dementia causing a significant reduction of quality of life of affected patients. In the brains of AD patients, ?-amyloid (A?) was identified as the main component of the amyloid plaques. Recently, deposits of A? have been documented in peripheral organs in AD and we provided evidence that the heart is one of the affected organs. We and others, have also shown that the complement system has a critical, non-redundant roles in creating and maintaining a non-inflammatory intravascular environment by tagging and opsonizing circulating foreign or abnormally folded host proteins with C1q, MBL, C3b and C4b. Importantly, free A?42 binds 3 out of 4 CR1 (complement receptor 1) ligands namely C1q, C3b and C4b. In the presence of complement A?42, binds CR1 on circulating RBCs. Unique to RBCs, the expression levels of CR1 are genetically determined, with individuals expressing either 90 copies of CR1/RBC (L/low), 500 CR1 copies (HL/intermediate) or 1200 CR1 copies (H/high expressers). Recently, several reports using GWAS data, linked CR1 polymorphisms to an increased risk of late-onset AD, lending credence to the role for RBCs in AD pathogenesis. In AD patients an abnormal clearance in blood A? was recently suggested based on a shift in A? levels from liver to brain, heart and periphery. Based on these observations, the overall hypothesis of this application is that the genetically determined CR1 levels on circulating RBCs are critical in: a) binding and safely remove circulating A? and b) preventing the cell-free A? to translocate to the RBC cytosol and be delivered via exosomes to damage peripheral tissues such as the heart, leading to heart failure and, in turn, worsening AD. We will test and validate this hypothesis by: A) Investigating the role of RBC-CR1 levels in the distribution of A? in EVs, RBCs and free in blood. B) Defining the functional consequences of free vs. EVs bound A? shuttling between brain and heart using a lox-cre mouse model, and C) Validating the role of RBCs and EVs in AD pathogenesis using tissues samples from AD patients The results of this study support the future of use free and RBC-bound A?42 as biomarker reservoirs to stage disease progression and therapeutic progresses.
The purpose of this application is to investigate the role of complement, circulating red blood cells (RBCs), and red cell-derived extracellular vesicles (EVs) in pathogenesis of Alzheimer?s disease and the crosstalk between the central nervous system and the peripheral tissue. We will use in-vitro and in-vivo assays, human tissue samples and a mouse animal model to test our hypothesis.
