The lack of effective treatment for Alzheimer's disease (AD) has necessitated more accurate and earlier diagnostic tools as well as disease-modifying therapies. A major focus of the Koronyo-Hamaoui Lab is development of immune-modulation treatment approaches and the investigation of the role that innate immune cells, especially peripheral monocytes and macrophages, may play in CNS repair and regeneration. The team discovered that blood enrichment with bone marrow-derived CD115+ monocytes by adoptive transfer into the peripheral blood of transgenic murine models of AD, or immunization with altered myelin-derived antigens, led to marked attenuation of disease progression and preservation of cognitive function. These multifaceted immune modulation interventions were found to mobilize neuroprotective inflammatory myeloid cells to cerebral lesion sites, which effectively removed toxic metabolites including amyloid; beta- protein, regulated neuroinflammation (i.e. reduced alpha and elevated IL-10), and stimulated synaptogenesis and neurogenesis. Specific molecular mediators for the beneficial effects were further identified; among these are osteopontin (OPN; also called SPP1), the transcription factor early growth response protein 1 (Egr1; also known as NGFI-A), and insulin-like growth factor-1 (IGF-1). To enhance the capacity of these innate immune cells to resist AD pathology, the lab studied the effects of targeted over-expression of an Ab degrading enzyme, angiotensin-converting enzyme (ACE), to myelomonocytes in murine models of AD. Introduction of ACE overexpressing monocytes to blood circulation of AD-model mice resulted in substantial prevention of synaptic loss and cognitive decline as well as attenuation of AD-associated pathology including diminished vascular amyloidosis. Continued efforts concentrate on identification of novel therapeutic approaches through better understanding of immune-CNS interactions and innate-immune mechanisms of synaptic preservation involved in regulation of detrimental inflammation, clearance of pathogenic beta species, and tissue regeneration. Another major focus of the Koronyo-Hamaoui Lab has been to explore Alzheimer's-related pathological changes occurring in the neurosensory retina, an accessible CNS organ for noninvasive high-resolution live imaging. The Koronyo-Hamaoui team has identified and characterized for the first time ever the pathological hallmarks of AD, beta deposits, in retinas of human patients and in early stage cases. These findings have led the team to pioneer an innovative methodology of in vivo and noninvasive detection of retinal amyloid deposits by utilizing curcumin labeling. This noninvasive retinal beta plaque imaging was translated to humans and is currently being tested in multiple clinical trials. It has potential applications for earlier AD diagnosis and follow-up response to AD therapies. Currently, the team seeks to discover novel retinal biomarkers and compare them to brain pathology associated with AD. Recently, the team revealed an early and substantial apoptotic pericyte cell loss along with decreased vascular platelet-derived growth factor receptor-beta; (PDGFR beta;) expression that were associated with vascular amyloidosis in postmortem retinas from MCI and AD patients. These changes further correlated with cerebral pathology and cognitive status. These findings open up new questions related to Alzheimer's-related vascular pathology in the retina and the role of pericytes in clearance of retinal beta and AD pathogenesis.