case western reserve university




Alzheimerís Disease
Our work on Alzheimerís disease has been focused on understanding the biological basis of AD pathogenesis using mouse models of the disease and how we might translate this knowledge into new therapeutics.

Neuroinflammation and the biology of myeloid cells in the AD brain.
The AD brain is typified by a robust inflammatory response centered on parenchymal amyloid deposits. This response is mediated by the brainís tissue macrophages, which surround the plaques. Historically, these cells were identified as microglia, which populate the brain during development. However, new work has shown that the plaque associated cells are derived from blood borne monocytes which infiltrate the AD brain. Importantly, the presence of these peripherally derived myeloid cells in the brain is dependent upon expression of TREM2. TREM2 encodes a cell surface receptor expressed on myeloid cells, including both monocytes and microglia. We are generating new genetic models to investigate the biology of TREM2 and how it confers increased disease risk.

Nuclear Receptors in the AD brain.
Nuclear Receptors are ligand activated transcription factors that act broadly in the brain to regulate many aspects of cellular metabolism and immune cell phenotypes. The principal nuclear receptors in the brain are the PPARs, LXRs and NR4A receptors which form obligate heterodimers with RXR to form a functional transcription factor. Administration of agonists to these receptors to mouse models of AD results in amelioration of AD pathogenesis and improved memory and cognition. We are now studying the ability of these receptors to mediate neuroprotective effects, to clear soluble forms of amyloid and to alter myeloid cell phenotype in the brain of murine models of AD.

Translation into new therapeutics.
We have documented that several nuclear receptor agonists can reverse AD pathogenesis in mouse models of AD. One of these, bexarotene, was very efficient in clearing amyloid from the brain and improving cognition. Bexarotene is an agonist of RXR and is an FDA-approved drug. We have conducted a phase Ib trial of bexarotene in normal subjects and it is being tested in a Phase II trial by the Cleveland Clinic Lou Ruvo Center. We are working to optimize the formulation of bexarotene for Phase II/III clinical trials.

Autism and the ERK MAP kinases.
The laboratory has a long-standing interest in the roles of the ERK MAP kinases in the nervous system. We have developed murine lines in which ERK1 and ERK2 have been knocked out. Analysis of these mice has revealed unexpected roles for these enzymes in neural crest development, patterning of the developing brain and corticogenesis. The ERK knockouts phenocopy neuro-cardiofacial cutaneous, DiGeorge and related

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