DEVELOPMENT OF D-PINITOL IN THE TREATMENT OF ALZHEIMER'S DISEASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 阿尔茨海默病（AD）是老年人发病率和死亡率的主要原因，其特征在于认知障碍和神经病理学特征，包括β淀粉样蛋白（A）沉积、神经纤维缠结和脑炎症增加。汇聚的证据显示AD和胰岛素抵抗之间的关联。大量AD患者表现出空腹血浆胰岛素升高和胰岛素敏感性降低。这些发现得到了流行病学研究的支持，这些研究证明了非胰岛素依赖性2型糖尿病（NIDDM）（一种通常与胰岛素抵抗相关的病症）与记忆障碍和AD的风险增加之间的关联（Kuisisto等人，1997; Ott等人，1999年）。我们假设，当早期治疗时，AD中的胰岛素抵抗和相关脑反应可以用可耐受剂量的胰岛素增敏剂逆转，并且这种治疗还可以阻止并可能逆转AD型认知障碍的临床和神经病理学进展。D-松醇，一种被批准的食品补充剂，在人体研究中已被证明具有胰岛素增敏作用。此外，在临床前研究中，它干扰β淀粉样蛋白的积累，这是阿尔茨海默病病理发展的重要步骤。 假设： 驱动本申请的工作假设是，胰岛素增敏剂d-松醇在结构上与参与胰岛素介导的葡萄糖转运刺激的磷脂酰肌醇磷酸相关，可能通过抑制β-葡萄糖转运而有益地影响AD型淀粉样蛋白神经病理学。分泌酶活性在大脑中导致减少生成淀粉样蛋白A？1-42而A？1-40肽

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease (AD), a leading cause of morbidity and mortality in older adults, is characterized by cognitive impairment and neuropathological features, including beta amyloid (A ) deposition, neurofibrillary tangles, and increased cerebral inflammation. Convergent evidence has revealed an association between AD and insulin resistance. A substantial number of patients with AD demonstrate elevated fasting plasma insulin and reduced insulin sensitivity. These findings are supported by epidemiological studies that demonstrate an association between non-insulin dependent type-2 diabetes (NIDDM), a condition often associated with insulin resistance, and increased risk for memory impairment and AD (Kuisisto et al., 1997; Ott et al., 1999). We hypothesized that when treated early, insulin resistance and associated brain responses in AD may be reversible with tolerable doses of insulin sensitizer agents and that this treatment may also arrest, and potentially reverse, the clinical and neuropathological progression of AD type cognitive impairment. D-pinitol, an approved food supplement has been shown to have insulin-sensitizing effects in human studies. Moreover, in preclinical studies it interferes with the accumulation of beta amyloid, an important step in the development of Alzheimer's pathology. Hypothesis: The working hypothesis driving this application is that the insulin sensitizer agent d-pinitol, structurally related to the phosphatidylinositol phosphates that participate in insulin-mediated stimulation of glucose transport may beneficially influence AD-type amyloid neuropathology through inhibition of ?-secretase activity in the brain resulting in reduced generation of amyloidogenic A?1-42 and A?1-40 peptides