Age-related cognitive decline: a transgenic approach

描述(由申请人提供)：学习和记忆方面的缺陷与明显的病理无关，被认为是衰老的正常组成部分。据估计，65岁以上的人中约有40%患有某种与年龄相关的认知障碍。导致这些自然发生的与年龄相关的学习和记忆缺陷的潜在神经元变化的确切性质仍不清楚。然而，近年来出现了几个有希望的假说。其中最突出的是“大脑衰老和神经变性的钙调节失调假说”。这一假说认为，许多与年龄相关的神经元功能变化是胞浆游离钙稳态失调的结果。事实上，有重要的实验证据表明，在神经元活动期间，老年动物神经元中的细胞内钙水平升高。此外，有几条趋同的证据表明，钙的增加是由于L型电压敏感钙通道(L-VSCC)数量的增加，这种钙通道密度的增加与空间学习能力和工作记忆成绩的下降有关。综上所述，上述证据是令人信服的；然而，与年龄相关的神经元LVSCC表达上调实际上会导致认知障碍的假设尚未得到直接检验。为了直接验证这一假设，我们产生了转基因小鼠，在其中神经元L型钙通道亚单位Cav1.3可以以可诱导的、细胞类型的和区域特异性的方式过度表达。在年轻的转基因动物中，Cav1.3的过度表达可能会导致选择性和过早的认知障碍。这项提议的总体努力将是：1)在分子和生化水平上完成这些小鼠的初步表征，以及2)完成初步的行为表征。这些转基因小鼠有望在两个方面促进我们的知识。首先，它们将使我们能够直接测试这一假设，即与年龄相关的钙通道增加会导致认知障碍，而认知障碍往往伴随着衰老而来。其次，如果这一假设确实是正确的，那么这些小鼠将成为开发旨在改善因钙通道表达上调而引起的与年龄相关的认知障碍的治疗方法的宝贵工具。

DESCRIPTION (provided by applicant): Deficits in learning and memory which arise independent of overt pathology are considered to be a normal component of aging. It is estimated that about 40% of people over the age of 65 years suffer from some sort of age-related cognitive impairment. The exact nature of the underlying neuronal changes that give rise to these naturally occurring age-related learning and memory deficits remains unknown. However, in recent years several promising hypotheses have emerged. Prominent among them is the "calcium dysregulation hypothesis of brain aging and neuro-degeneration." This hypothesis asserts that a number of age-related changes in neuronal function are the result of a dysregulation in the homeostasis of cytosolic free calcium. Indeed there is significant experimental evidence demonstrating an elevated level of intracellular calcium in the neurons of aged animals during neuronal activity. Furthermore, there are several lines of converging evidence that suggest that the increase in calcium is due to an increase in the number of L-type voltage-sensitive calcium channels (L-VSCC), and this increase in calcium channel density is correlated with a decrease in performance in spatial learning ability and working memory. Taken collectively, the evidence outlined above is compelling; however, the hypothesis that an age-related up-regulation of neuronal LVSCC expression can actually cause cognitive impairment has yet to be tested directly. To directly test this hypothesis, we have generated transgenic mice in which the neuronal L-type calcium channel subunit Cav1.3 can be over-expressed in an inducible, cell-type and region-specific manner. In young transgenic animals, over-expression of Cav1.3 would be expected to produce a selective and premature cognitive impairment. The overall effort of this proposal will be to: 1) complete the initial characterization of these mice at the molecular and biochemical level, and 2) complete the initial behavioral characterization. These transgenic mice are expected to advance our knowledge on two fronts. First, they will allow us to test directly the hypothesis that age-related increases in calcium channels can give rise to the cognitive impairments that often accompany aging. Second, if this hypothesis is indeed correct, these mice will then become an invaluable tool in the development of therapies targeting the amelioration of age-related cognitive impairments that arise from up-regulation of calcium channel expression.