A major focus of my research is the development of immune-modulation treatments for Alzheimer’s
disease (AD). My laboratory investigates the role of innate immune cells – especially peripheral monocytes and macrophages – in CNS repair and regeneration. This approach presents a paradigm shift away from the common view that any involvement of peripheral immune cells in the brain is a sign of pathology. My team recently discovered that instead of being detrimental, recruitment of a subset of bone marrow (BM)-derived
monocytes into the brain can lead to marked attenuation of disease progression in transgenic murine models of AD. This effect was achieved by either adoptive transfer of young BM-derived CD115+LyC6hi monocytes to the peripheral blood of symptomatic transgenic AD mice, or immunization with altered myelin-derived antigens. This multifaceted immune modulation intervention was found to substantially regulate neuroinflammation, diminish various neuropathologies associated with AD, and remarkably rescue synapses as well as cognitive function. To enhance the capacity of innate immune cells to resist AD pathology, the lab
has explored several strategies. These include stimulation of monocytes with an FDA-approved drug (glatiramer acetate) and the genetic targeting of angiotensin-converting enzyme (ACE), a peptidase capable of degrading neurotoxic forms of Aβ, to myelomonocytes in murine models of AD. Both the pharmacological and the genetic approaches resulted in substantial prevention of cognitive decline and attenuation of associated pathology. The immune mechanisms involved regulation of detrimental inflammation, enhanced uptake and degradation of pathological Aβ assemblies, reduced cerebral vascular and parenchymal Aβ deposits, resolution of scar tissue proteins, restoration of astrocyte phenotype, and preservation of synapses by these modified young monocytes. We have also demonstrated that replacing AD bone marrow with young
wild type marrow attenuates disease progression, which was further enhanced by ACE overexpressing monocytes, while depleting these cells in the blood accelerates disease progression. Another emphasis of my research is on early diagnosis of AD through retinal imaging. My team identified the pathological hallmarks of AD, amyloid β-protein (Aβ) plaques, in the human retina. Moreover, we developed a novel approach for in vivo detection of retinal Aβ deposits in live rodent models, allowing for noninvasive, high-resolution monitoring of individual plaques during disease progression. Our imaging method has now been validated in a proof-of-concept clinical trial and is currently undergoing further testing in several large-scale cohorts.