Targeting cellular prion protein reverses early coanitive deficits and neurophysiological dysfunction in prion-infected mice
Targeting cellular prion protein reverses early coanitive deficits and neurophysiological dysfunction in prion-infected mice
复制标题
DOI：
10.1016/j.neuron.2007.01.005
复制
发表时间：
2007-02-01
期刊：
影响因子：
16.2
通讯作者：
Collinge, John
中科院分区：
文献类型：
--
作者：
Mallucci, Giovanna R.;White, Melanie D.;Collinge, John
目前，尚无治疗方法可以预防与朊病毒病中广泛的神经变性相关的认知和运动能力下降。然而，我们之前表明，在早期朊病毒感染的小鼠中，针对内源性神经元朊病毒蛋白（PrPc）（其疾病相关异构体 PrPsc 的前体）可逆转海绵状变化，并防止临床症状和神经元损失。我们现在表明，早期海马海绵状病理伴随着认知和行为缺陷以及神经生理功能受损。值得注意的是，当神经元 PrPc 耗尽时，这些行为和突触损伤就会恢复，同时海绵组织增生也会逆转。因此，朊病毒病中的早期功能损伤先于神经元损失，并且是可以挽救的。此外，它们发生在大量 PrPsc 沉积物积累之前，并在 PrPc 耗尽后迅速恢复，这支持了它们是由短暂的神经毒性物质引起的概念，与聚集的 PrPsc 不同。这些数据表明，对人类朊病毒病的早期干预可能会导致认知和行为症状的恢复。
Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrPc) (the precursor of its disease-associated isoform, PrPsc) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrPc is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrPsc deposits accumulate and recover rapidly after PrPc depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrPsc. These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.