PROTEOGLYCAN METABOLISM IN AGING AND DEMENTIA

目前的建议是基于越来越多的证据， 表明硫酸乙酰肝素蛋白聚糖（HSPG）在 淀粉样变性 HSPGs在老年性痴呆-Alzheimer型中的共沉积 β-淀粉样肽（Abeta）来源于 β-淀粉样前体蛋白（betaPP）和载脂蛋白E（apoE）， SDAT的风险因素。 apoE和betaPP/Abeta均结合HSPG。 然而，在这方面， 由于HSPG、β PP/Abeta和apoE都是正常细胞产物， 在SDAT中，一定有促进淀粉样蛋白病理性沉积的因素。 的 申请人已经假设，老化大脑中的炎症和修复 可能导致HSPG代谢紊乱，促进淀粉样蛋白形成。 他们已经表明，炎症和修复因子增加了硫酸化 和HSPGs的分泌。 这种HSPGs的“过度硫酸化”和“过度分泌” 可以通过多种可能的机制促进淀粉样蛋白的形成。 的 目前的资助将在组织培养模型中进一步探索这一假设 采用海马神经元的原代培养物;在动物模型中 采用立体定向侧脑室注射;在人脑中， 尸检对照组和SDAT患者。 在这三种范式中， 申请人将研究细胞因子（白细胞介素-1）和生长的作用， 因子（神经生长因子和转化生长因子-β 1） HSPG和磺基转移酶活性的硫酸化;以及 特异性HSPG（串珠素）mRNA和蛋白质核心分泌。 此外，本发明还提供了一种方法， 他们将研究这些细胞因子和生长因子对 HSPG对β PP、Abeta和apoE表型的结合亲和力。 最后，在动物模型和人脑标本中， 研究炎症和修复对炎症的影响的假设， 随着年龄的增长，HSPG代谢失调，这进一步倾向于 老化的机体形成淀粉样蛋白。

DESCRIPTION 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.