Amyloid beta (Abeta), the major constituent of the amyloid fibrils deposited in cerebral blood vessels and parenchymal plaques Alzheimer s brains, is also normally found as a soluble component (sAbeta) in biological fluids, where it appears to be transported (greater than 90 percent) in association with lipoprotein particles. Although peptides homologous to sAbeta spontaneously polymerize in vitro, the potential contribution of the circulating soluble forms to the deposited Abeta remains unknown. It has been demonstrated that the blood brain barrier has the capability to modulate the uptake of Abeta species and that the interaction of Abeta with carrier apolipoproteins E and J results in either prevention or enhancing of the brain uptake respectively. In addition, an increased amount of sAbeta was found in soluble fractions of Alzheimer s disease and Down s syndrome brain homogenates, and this elevation appears to precede the appearance of Abeta deposits. The overall goal of this proposal is to investigate the contribution of circulating Abeta peptides to the vascular pathology observed in aging, Alzheimer s disease and related disorders. The knowledge of physiologic aspects of sAbeta turn-over, among them the peptide s half-life in circulation, its interaction(s) with circulating transport molecules, the organs involved in its catabolism and/or excretion and the putative cerebrovascular cell receptors responsible for its uptake by the cerebral vessel wall as well as how these physiologic parametes are modulated under pathologic situations will certainly contribute to better understanding of the mechanism(s) leading to the formation of vascular and perhaps parenchymal amyloid deposits. The four specific aims outlined in the project are focused a) to identify cell receptors for free and complexed Abeta species in cerebral endothelial cells (aim 1), b) to investigate the half- life of free and complexed Abeta species in circulation as well as to determine their systemic sites of catabolism and/or excretion (aim 2), c) to ascertain whether oxidation of the carrier lipoparticle may favor complexdisequilibrium resulting either in the release of free sAbeta or in the formation of oxidized Abeta (aim 3), and d) to clarify whether the physiologic variables evaluated in aims 1 and 2 are compromised in aging and Alzheimer s disease (aim 4).
| Ovodenko, Boris; Rostagno, Agueda; Neubert, Thomas A et al. (2007) Proteomic analysis of exfoliation deposits. Invest Ophthalmol Vis Sci 48:1447-57 |
| Lashley, T; Holton, J L; Verbeek, M M et al. (2006) Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene-related dementias: a morphological study. Neuropathol Appl Neurobiol 32:492-504 |
| Fotinopoulou, Angeliki; Tsachaki, Maria; Vlavaki, Maria et al. (2005) BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production. J Biol Chem 280:30768-72 |
| Matsuda, Shuji; Giliberto, Luca; Matsuda, Yukiko et al. (2005) The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. J Biol Chem 280:28912-6 |
| Rostagno, A; Tomidokoro, Y; Lashley, T et al. (2005) Chromosome 13 dementias. Cell Mol Life Sci 62:1814-25 |
| Calero, Miguel; Rostagno, Agueda; Frangione, Blas et al. (2005) Clusterin and Alzheimer's disease. Subcell Biochem 38:273-98 |
| Morelli, Laura; Llovera, Ramiro E; Alonso, Leonardo G et al. (2005) Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia. Biochem Biophys Res Commun 332:808-16 |
| Tomidokoro, Yasushi; Lashley, Tammaryn; Rostagno, Agueda et al. (2005) Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques. J Biol Chem 280:36883-94 |
| Morelli, Laura; Llovera, Ramiro E; Mathov, Irina et al. (2004) Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid {beta} vasculotropic variants and reduced activity in cerebral amyloid angiopathy. J Biol Chem 279:56004-13 |
| Ghiso, Jorge; Shayo, Marcos; Calero, Miguel et al. (2004) Systemic catabolism of Alzheimer's Abeta40 and Abeta42. J Biol Chem 279:45897-908 |
Showing the most recent 10 out of 19 publications
