Abstract
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, ß-amyloid (Aß) was identified as the
main component of the amyloid plaques. Recently, deposits of Aß 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
Aß42 binds 3 out of 4 CR1 (complement receptor 1) ligands namely C1q, C3b and C4b. In the
presence of complement Aß42, 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 Aß was recently suggested based on a shift in Aß 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 Aß
and b) preventing the cell-free Aß 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 Aß in EVs, RBCs and free in blood. B) Defining the functional consequences of free vs. EVs bound
Aß 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 Aß42 as biomarker
reservoirs to stage disease progression and therapeutic progresses.
