Abnormalities in the Processing of the Amyloid Precursor Protein in Alzheimer's Disease
Extraordinary progress has been made in the past decade toward understanding and diagnosing the memory and cognitive dysfunctions that define the progressive dementia characteristic of Alzheimer's disease (AD). However, the underlying causes and possible treatments and cure for AD remain elusive. Our laboratory uses cellular, biochemical and molecular technologies to investigate the causes of AD. We focus on the structural and functional properties of, and interactions between, two proteins that are genetically, pathologically, and biochemically linked to AD: amyloid-ß (Aß) and apolipoprotein E (apoE).
Abnormalities in the processing of amyloid precursor protein to Aß are causal factors and the presence of the e4 allele of apoE is the primary risk factor for Alzheimer’s disease (AD). Based at least in part on these genetics, the potential structural and functional interactions between these two proteins are the focus of our research. Because the biological activities for both apoE and Aß are profoundly influenced by their isoform and conformation, respectively, our research focuses on how apoE3 and E4 differentially interact with particular assembly species of Aß 1-42. Our overall hypothesis is that apoE3 interacts with oligomeric Aß to block Aß-induced neuroplasticity, neurotoxicity and neuroinflammation, while apoE4 actually potentiates the negative effects of oligomeric Aß. In addition, apoE receptors participate in this process by binding and clearing apoE3:Aß oligomer complexes.
Selected References
Manelli, A.M., Bulfinch, L., Sullivan, P.M. and LaDu, M.J. (2006) Effect of Aß structure and human apoE isoform on primary co-cultures of neurons and glia. Neurobiology of Aging, In press.
LaDu, M.J., Stine, W.B., Narita, M, Getz, G.S., Reardon, C.A. and Bu, G. (2006) Self-assembly of HEK cell-secreted apoE particles resemble apoE-enrichment of lipoproteins as a ligand for the LDL receptor-related protein. Biochemistry 45:381-390.
White, J.A., Manelli, A.M., Holmberg, K.H., Van Eldik, L.J. and LaDu, M.J. (2005) Differential effects of oligomeric and fibrillar amyloid-ß 1-42 on glia-mediated inflammation. Neurobiology of Disease 18:459-465.
Trommer, B.L., Shah, C., Gamkrelidze, G., Yun, S.H., Pasternak, E.S., Stine, B., Manelli, A., Sullivan, P., Pasternak, J.F. and LaDu, M.J. (2005) Apolipoprotein E isoform-specific effects on LTP: blockade by oligomeric amyloid-ß. Neurobiology of Disease 18(1):75-82.
Stine Jr., W.B., Dahlgren, K.D., Krafft, G.A. and LaDu, M.J. (2003) In vitro characterization of conditions for Aß-peptide oligomerization and fibrillogenesis. J. Biol. Chem. 278:11612-11622.
Dahlgren, K.D., Manelli, A.M., Stine Jr., W.B., Baker, L.K., Krafft, G.A. and LaDu, M.J. (2002) Oligomeric and fibrillar species of amyloid- ß peptides differentially affect neuronal viability. J. Biol. Chem. 277:32046-32053.
