DARC, Inflammaging and Alzheimer's Disease

PROJECT SUMMARY Chronic inflammation of the brain occurs with aging and plays an important role in age-related cognitive decline and Alzheimer’s disease (AD) progression. Proinflammatory chemokines not only bind to their cognate receptors, but also to “atypical” chemokine receptors (ACKR) that lack intracellular signaling domains and principally serve to buffer or control chemokine bioavailability. The Duffy Antigen Receptor for Chemokines (DARC) is a member of the ACKR subfamily. DARC is highly expressed on red blood cells (RBCs), and to a lesser extent in other cell types, where it functions as a chemokine ‘buffer-sink’, sequestering proinflammatory chemokines. There are two dominant DARC alleles in humans, Fyb (predominant in European Caucasians) and Fya (hypofunctional allele prevalent in Asians). A mutation in the promoter region of the Fyb allele abolishes the expression of DARC in RBC. Notably, approximately 70% of African Americans harbor this mutation, which is associated with a pro- inflammatory phenotype. We provide novel preliminary data showing that both global DARC knockout mice, and mice lacking DARC selectively in blood cells, exhibit cognitive impairment and increased levels of proinflammatory mediators associated with AD. Moreover, DARC is downregulated in the brain with aging and in AD mice, and overexpression of mouse DARC in the brain alleviated cognitive impairment in 5xFAD mice, supporting that DARC protects against AD-related cognitive decline. These novel findings lead us to hypothesize that DARC plays an important role in regulating neuroinflammation, cognitive dysfunction and AD pathologies. To test this hypothesis, we propose three specific aims. In Aim 1, we will determine if selective ablation of DARC in blood cells accelerates age-related neuroinflammation and cognitive decline and exacerbates neuropathological and cognitive phenotypes of AD mice. In Aim 2, we will determine if ablation or overexpression of mouse DARC in forebrain glutamatergic neurons modulates neuronal vulnerability to degeneration, Aβ/tau pathologies, and aging- and AD-associated cognitive impairment. In Aim 3, we will determine if DARC-Fya and Fyb isoforms differ in their ability to sequester chemokines and Aβ and their protective effects against neuroinflammation and cognitive impairment.