Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, 2360102 Valparaíso, Chile.
Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13835-40. doi: 10.1073/pnas.1201209109. Epub 2012 Aug 6.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是进行性记忆丧失、严重痴呆和标志性神经病理学标志物，如淀粉样β（Aβ）肽在老年斑中的沉积和过度磷酸化的 tau 蛋白在神经原纤维缠结中的积累。最近从转基因小鼠模型中获得的证据表明，可溶性、无纤维 Aβ 寡聚体可能会在 AD 早期引起突触功能障碍。尽管这些转基因模型具有不可否认的价值，但它们依赖于遗传操作，代表了遗传性和家族性的 AD，但不是最常见的散发性 AD。开发具有 AD 特征的非转基因动物模型将是理解散发性 AD 如何发生的重要一步。在这里，我们表明，从 12 到 36 月龄开始，啮齿动物毛丝鼠自然会出现 AD 的神经病理学迹象，如 Aβ 寡聚体和磷酸化 tau 蛋白的积累。此外，Aβ 寡聚体和 tau 磷酸化水平与空间和物体识别记忆、突触后功能和突触可塑性的下降呈年龄相关性变化。这些发现验证了毛丝鼠作为研究散发性 AD 如何发生的合适的天然模型。
