Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease
Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease
复制标题
DOI：
10.1073/pnas.1201209109
复制
发表时间：
2012-08-21
影响因子：
11.1
通讯作者：
Palacios, Adrian G.
中科院分区：
文献类型：
--
作者：
Ardiles, Alvaro O.;Tapia-Rojas, Cheril C.;Palacios, Adrian G.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其与进行性记忆丧失、严重痴呆和标志性神经病理学标志物（例如老年斑中淀粉样蛋白-β（A β）肽的沉积和神经元缠结中过度磷酸化的tau蛋白的积累）相关。最近从转基因小鼠模型中获得的证据表明，可溶性非纤维状A β寡聚体可能在AD早期诱导突触失效。尽管这些转基因模型具有明显的价值，但它们依赖于代表遗传性和家族性的遗传操作，而不是最丰富的散发性AD形式。一个非转基因的动物模型，仍然发展标志性的AD将是一个重要的一步，了解散发性AD是如何启动的。在这里，我们表明，从12至36个月的年龄开始，啮齿类动物Dendon degus自然发展出AD的神经病理学体征，如A β寡聚体和磷酸化tau蛋白的积累。此外，A β寡聚体和tau磷酸化水平的年龄相关变化与空间和物体识别记忆、突触后功能和突触可塑性的降低相关。这些发现验证了O. degus作为一个合适的自然模型，研究如何散发性AD可能启动。
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-beta (A beta) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar A beta 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 A beta oligomers and phosphorylated tau proteins. Moreover, age-related changes in A beta 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.