PROTEOGLYCAN METABOLISM IN AGING AND DEMENTIA

衰老和痴呆中的蛋白聚糖代谢

基本信息

批准号：
2771960
负责人：
MARIANN M BLUM
金额：
$ 19.65万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-30 至 1999-08-31
项目状态：
已结题

项目摘要

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.

描述本提案基于越来越多的证据表明硫酸乙酰肝素蛋白聚糖 (HSPG) 在淀粉样蛋白生成。 HSPGs在老年性痴呆-阿尔茨海默氏症中共同沉积 (SDAT) 大脑，含有源自β-淀粉样肽 (Abeta) 的 β-淀粉样蛋白前体蛋白 (betaPP) 和载脂蛋白 E (apoE) SDAT 的危险因素。 apoE 和 betaPP/Abeta 均结合 HSPG。然而，由于HSPG、betaPP/Abeta和apoE都是正常的细胞产物，其他一定因素促进淀粉样蛋白在SDAT中病理性沉积。这申请人假设衰老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。他们表明炎症和修复因子会增加硫酸盐化和 HSPG 的分泌。 HSPG 的“过度硫酸化”和“过度分泌” 可能通过多种可能的机制促进淀粉样蛋白的形成。这目前的资助将在组织培养模型中进一步探讨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；并在人脑中尸检对照受试者和 SDAT 患者。在所有三种范式中，申请人将研究细胞因子（白介素-1）和生长的影响因子（神经生长因子和转化生长因子-β1） HSPG 的硫酸化和磺基转移酶活性；以及关于上调特定的 HSPG (perlecan) mRNA 和蛋白质核心分泌。此外，他们将研究这些细胞因子和生长因子对 HSPG 对 betaPP、Abeta 和 apoE 表型的结合亲和力。最后，在动物模型和人脑标本中，他们将研究炎症和修复的影响的假设 HSPG 代谢随着年龄的增长而失调，这进一步导致衰老的有机体促进淀粉样蛋白的形成。