The present proposal is based on the increasing evidence indicating that heparan sulfate proteoglycans (HSPGs) play a key role in amyloidogenesis. HSPGs are co-deposited in senile dementia-Alzheimer's type (SDAT) brain with the beta-amyloid peptide (Abeta) derived from the beta-amyloid precursor protein (betaPP), and with apolipoprotein E (apoE), a risk factor for SDAT. Both apoE and betaPP/Abeta bind HSPGs. However, since HSPGs, betaPP/Abeta and apoE are all normal cellular products, other factors must promote the pathological deposition of amyloid in SDAT. The applicants have postulated that inflammation and repair in the aging brain may result in disordered metabolism of HSPGs to promote amyloid formation. They have shown that inflammation and repair factors increase the sulfation and secretion of HSPGs. This 'hypersulfation' and 'hypersecretion' of HSPGs may promote amyloid formation by a number of possible mechanisms. The current grant will explore this hypothesis further in a tissue culture model employing primary cultures of hippocampal neurons; in an animal model employing stereotactic lateral ventricle injections; and in human brain from autopsies control subjects and patients with SDAT. In all three paradigms, the applicants will study the effect of cytokines (interleukin-1) and growth factors (nerve growth factor and transforming growth factor-beta1) on the sulfation of HSPG and sulfotransferase activity; and on the upregulation of a specific HSPG (perlecan) mRNA and protein core secretion. In addition, they will investigate the effect of these cytokines and growth factors on the binding affinity of HSPG for betaPP, Abeta, and apoE phenotypes. Finally, in the animal model and in human brain specimens, they will investigate the hypothesis that the effects of inflammation and repair on HSPG metabolism are dysregulated with aging, and this further predisposes the aging organism to amyloid formation.
| Garcia de Yebenes, E; Ho, A; Damani, T et al. (1999) Regulation of the heparan sulfate proteoglycan, perlecan, by injury and interleukin-1alpha. J Neurochem 73:812-20 |
| Leveugle, B; Ding, W; Laurence, F et al. (1998) Heparin oligosaccharides that pass the blood-brain barrier inhibit beta-amyloid precursor protein secretion and heparin binding to beta-amyloid peptide. J Neurochem 70:736-44 |
