Landreth Lab

Biology of neuroinflammation in Alzheimer’s disease

The AD brain is typified by a robust inflammatory response mediated ‘activated’ plaque-associated microglia, and this response is postulated to contribute to cognitive impairment and ultimately neuronal death. The Landreth Lab was amongst the first team of medical scientists to identify the receptors for fibrillar forms of Alzheimer’s disease. The team identified an ensemble of receptors, including scavenger receptors, TLRs and their coreceptors, which act in concert to bind amyloid fibrils and initiate microglial responses through multiple parallel signal transduction pathways. The lab has validated its involvement by genetic inactivation of the fA receptors and signaling elements. Significantly, these scientists recently reported that the plaque associated macrophages are not resident microglia but derive from blood borne monocytes that invade the AD brain and specifically associate with plaques and mediate the proinflammatory response that typifies the disease. The laboratory is currently working to understand the diverse nature of the inflammatory response and how it might simultaneously exacerbate or ameliorate the various aspects of the disease.

Roles of Nuclear Receptors in CNS disorders

Nuclear receptors are ligand-activated transcription factors that act broadly to regulate metabolism as well as myeloid cell phenotype. Scientists in the Landreth Lab were the first to document the efficacy of agonists of these receptors in CNS disorders, most prominently Alzheimer’s disease. The lab team demonstrated that nuclear receptor agonists improved AD-related phenotypes and improved learning and memory in animal models of disease. The work catalyzed a large number of studies, both in my laboratory and by others, in various animal models of CNS disorders. Importantly, these medical scientists translated this work into clinical trials of PPAR and RXR agonists in AD, and there are now several phase II and phase III trials of nuclear receptor agonists underway in several CNS disorders. The lab is currently investigating new drug candidates that target these receptors.

Roles of apolipoprotein E in Alzheimer’s disease pathogenesis

One of the principal unanswered questions in Alzheimer’s disease pathogenesis is how a variant of the apolipoprotein E gene, ApoE4, confers dramatically elevated risk for the disease. Investigators in the Landreth Lab found that ApoE acts physiologically to promote the proteolytic degradation of ApoE, and the ApoE4 isoform is impaired in this function. Importantly, induction of ApoE expression by PPARor RXR agonists resulted in enhanced clearance of soluble forms of A that was accompanied by improved neural network function and reversal of cognitive deficits in mouse models of AD. ApoE is also involved in a number of other disease related processes and the laboratory is interested in elucidating its multiple roles in AD pathogenesis.