Epidemiological studies have demonstrated that AD is a complex disorder with numerous proposed genetic and environmental etiologies and that the disease likely begins in the brain decades before the onset of clinical symptoms. Given this, it is not surprising that there is considerable variation in the duration, severity, symptoms, age of onset and clinical/neuropathological correlations of AD. However, the fact that AD is a late-onset neurodegenerative disease with no accurate diagnostic markers makes the study and identification of the genetic, environmental and therapeutic factors that modify risk for AD exceedingly difficult. Given these difficulties my laboratory has turned to the mouse as a genetically defined and tractable model to study AD phenotypes. Over the past several years my laboratory has focused on developing and characterizing genomic-based mouse models of AD (“genocopies”), through the introduction of complete copies of human AD genes into the germline of mice. These includes models that exhibit the beta-amyloid pathology observed in AD (termed R1.40) and another model that exhibit the microtubule-associated protein tau pathology observed in AD and also other neurodegnerative tauopathies (termed hTau). The current studies in my laboratory focus on utilizing these genomic-based transgenic mouse models of AD to identify and characterize modifiers of AD phenotypes focusing on; 1) genetic modifiers identified from both mouse and human studies, 2) microglia and neuronal-microglial communication in the development and progression of AD pathologies; and 3) traumatic brain injury as an environmental modifier for the development of AD pathologies.
Varvel, N.H., Bhaskar, K., Kounnas, M.Z., Wagner, S.L., Yang, Y., Lamb, B.T., and K. Herrup. NSAIDs prevent, but do not reverse, neuronal cell cycle re-entry in Alzheimer’s disease mouse models. 119:3692-3702, JCI, 2009.
Bhaskar, K., Konerth, M.E., Kokiko-Cochran, O.N., Cardona, A.E., Ransohoff, R.M., and B.T. Lamb. Regulation of tau pathology by the microglial fractakine receptor. Neuron, 68:19-31, 2010.
Lee, S., Varvel, N.H., Konerth, M.E., Xu, G., Cardona, A.E., Ransohoff, R.M., and B.T. Lamb. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol, 177:2549-2562, 2010.
Cameron, B. Tse, W., Lamb, R., Li, X., Lamb, B.T., and G.E. Landreth. Loss of interleukin receptor associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer’s Disease. J Neurosci 32:15112-15123, 2012.