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多糖(HSPGs)在 淀粉样变。老年性痴呆-阿尔茨海默型患者HSPG共沉积 (SDAT)大脑中的β-淀粉样多肽(Abeta)来源于 β-淀粉样前体蛋白(β-PP)和载脂蛋白E(ApoE)，a SDAT的风险因素。ApoE和βPP/Aβ均可与HSPG结合。然而， 由于HSPG、βPP/Abeta和apoE都是正常的细胞产物，其他 在SDAT中，一定有促进淀粉样蛋白病理性沉积的因素。这个 申请者假设老化的大脑中的炎症和修复 可能导致HSPG代谢紊乱，促进淀粉样蛋白的形成。 他们已经证明，炎症和修复因素会增加硫酸盐化。 和HSPG的分泌。HSPG的这种“过硫化”和“高分泌” 可能通过一些可能的机制促进淀粉样蛋白的形成。这个 目前的格兰特将在组织培养模型中进一步探索这一假设。 利用原代培养的海马神经元；动物模型 使用立体定向侧脑室注射；在人脑中 尸检对照受试者和SDAT患者。在所有三个范例中， 申请者将研究细胞因子(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)对血管生成的影响 硫酸盐化HSPG和磺基转移酶活性；以及上调HSPG 一种特异的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与βPP、Abeta和apoE表型的结合亲和力。 最后，在动物模型和人脑样本中，它们将 研究炎症和修复对疾病影响的假设 随着年龄的增长，HSPG代谢失调，这进一步使 衰老的有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.