CHOLINERGIC BASAL FOREBRAIN NEUROTROPHIC ABNORMALITES & MILD COGNITIVE IMPAIRMENT

描述(由申请人提供)：潜在的病理事件 从轻度到轻度转变过程中特定神经元群体的退化 认知障碍(MCI)到阿尔茨海默病(AD)仍不清楚。我们 已证明大鼠双侧丘脑基底核亚区的神经元 胆碱能基底前脑(CBF)表现出表型差异 非认知功能障碍人群化学标志物的表达 和MCI。例如，显示胆碱的CBF神经元的数量 乙酰基转移酶(ChAT)与囊泡乙酰胆碱转运体 免疫反应性被保留(39)，而包含 高亲和力(TrkA)信号转导NGF受体蛋白和基因 在MCI(17，82)中显著降低。这些观察结果表明 神经营养素的变化是痴呆症的早期标志。有趣的是， ChAT活性在MCI个体(24，28)的大脑皮层中保持稳定， 提示胆碱能合成在下丘脑神经元内仍有功能。 这些人体内的CBF。相比之下，尚不清楚皮质TrkA MCI中的水平降低，因为它们处于AD末期(58，83)。如果TrkA水平 在MCI患者的大脑皮层中保持稳定，这表明非CBF TrkA受体阳性细胞，如皮质中的胶质细胞，是 补偿CBF中这种受体产生的减少 MCI患者的神经元。除了TrkA，其他与NGF相关的蛋白质 可能导致CBF神经元在疾病进展过程中的脆弱性 痴呆症。有趣的是，我们发现与NGF相关的数量减少了 含NUR77的CBF神经元及其合成障碍 MCI和AD患者的CBF神经元进一步减少。这是在 与我们的发现相反，TrkA阳性CBF神经元的减少并不是 AD组较MCI组加速(17，82)。因此，特定目标2将 检验CBF Nur77免疫阳性神经元数量为 在患有MCI的人中减少，这种损失在AD时加剧。此外， 我们将研究在MCI患者中Nur77的合成是否减少。 与脑血流量退化相关的另一个候选因素是微管。 蛋白tau，它累积形成神经原纤维缠结 (NFTS)。在临床前AD(94,102)中，CBF神经元被NFT包裹。 因此，一种常见的假设是tau在NFT中的积累导致 细胞蛋白质和基因功能障碍，最终导致细胞死亡(43，44,115)。 Tau蛋白的积累对人骨肉瘤基因特征的影响 MCI中单个CBF神经元以及它是否与AD不同尚不清楚。 具体目标3将检验存在选择性下调监管的假设 CBF NFT神经元与非NFT神经元基因转录物类别的比较 在从NCI向MCI过渡的过程中。这些研究将为以下工作提供数据 设计有效的药物遗传疗法。

DESCRIPTION (provided by applicant): The pathological events underlying degeneration of select populations of neurons during the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain unknown. We have demonstrated that the neurons of the nucleus basalis subfield of the cholinergic basal forebrain (CBF) display phenotypic differences in their expression of chemical markers in people with no cognitive impairment (NCI) and MCI. For example, the number of CBF neurons displaying choline acetyltransferase (CHAT) and vesicular acetylcholine transporter immunoreactivity are preserved (39), whereas CBF neurons containing the protein and gene for the high affinity (trkA) signal transduction NGF receptor are significantly reduced in MCI (17,82). These observations suggest that alterations in neurotrophins are an early marker for dementia. Interestingly, ChAT activity remains stable in the cortex of MCI individuals (24,28), suggesting that cholinergic synthesis is still functional within neurons of the CBF in these people. In contrast, it is not known whether cortical trkA levels are reduced in MCI as they are in end stage AD (58,83). If trkA levels remain stable in the cortex of MCI people, this would suggest that non-CBF trkA receptor positive cells, such as glial cells in the cortex, are compensating for the reduction in the production of this receptor seen in CBF neurons of people with MCI. In addition to trkA, other NGF-related proteins may contribute to the vulnerability of CBF neurons in the progression of dementia. Interestingly, we have found a reduction in the number of NGFrelated Nur77 containing CBF neurons as well as impaired synthesis of Nur77 in CBF neurons in people with MCI and a further reduction in AD. This is in contrast to our finding that the reduction of trkA positive CBF neurons is not accelerated in AD as compared to MCI (17,82). Therefore, Specific Aim 2 will test the hypothesis that the number of CBF Nur77 immunopositive neurons are reduced in people with MCI and that the loss is exacerbated in AD. Moreover, we will examine whether the synthesis of Nur77 is reduced in people with MCI. Another candidate associated with CBF degeneration is the microtubuleassociated protein tau, which accumulates to form neurofibrillary tangles (NFTs). CBF neurons are invested with NFTs in preclinical AD (94, 102). Thus, a common hypothesis is that accumulation of tau into NFTs results in cellular protein and gene dysfunction and ultimately cell death (43,44,115). The effect that the accumulation of tau has on the genetic signature of individual CBF neurons in MCI and whether it differs from AD is not known. Specific Aim 3 will test the hypothesis that there is a selective downregulation of classes of gene transcripts in CBF NFT versus non-NFT neurons during the transition from NCI to MCI. These studies will provide data to devise effective pharmacogenetic therapies.