Interactions between Aβ oligomers and presynaptic cholinergic signaling: age-dependent effects on attentional capacities.
Interactions between Aβ oligomers and presynaptic cholinergic signaling: age-dependent effects on attentional capacities.
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DOI：
10.1016/j.bbr.2014.07.046
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发表时间：
2014-11-01
影响因子：
2.7
通讯作者：
Yegla, Brittney
中科院分区：
文献类型：
--
作者：
Parikh, Vinay;Bernard, Carcha S.;Naughton, Sean X.;Yegla, Brittney
大量证据表明，神经毒性纤维形式的淀粉样前体蛋白β-淀粉样蛋白(Aβ)在阿尔茨海默病(AD)的发病机制中发挥着关键作用。然而，AD病理的许多方面，包括皮质投射的基底前脑(BF)胆碱能神经元的认知症状和选择性易损性，并不能很好地解释这一假说。具体地说，尚不清楚为什么在AD晚期表现出BF胆碱能神经元的丢失和斑块沉积时，认知能力下降会出现得更早。Aβ的可溶寡聚体形式被认为是在病理早期出现的，并且可以更好地预测突触丢失和认知障碍。本研究旨在探讨A-β寡聚体对幼年和老年大鼠注意功能和突触前胆碱能传递的影响。长期脑内注射Aβ寡聚体使大鼠在工作时间内保持注意力的能力略有下降，而与动物的年龄无关。然而，在老年动物注意力负荷增加的情况下，Aβ寡聚体对表现产生了强烈的有害影响。体内电化学记录显示，注入β的老年大鼠去极化诱发的胆碱能信号减少。此外，可溶性Aβ干扰了幼年和老年大鼠胆碱能突触清除细胞外间隙外源性胆碱的能力，反映了胆碱运输过程中的损害，胆碱运输过程是乙酰胆碱(ACh)合成和释放的关键。尽管衰老本身降低了大脑皮质BF胆碱能神经元和突触前胆碱能蛋白的横截面积，但注射对照多肽的老年大鼠的注意行为和ACh释放没有受到影响。综上所述，这些数据表明，可溶性Aβ可能主要通过干扰胆碱摄取过程而对年轻时的注意功能产生轻微影响。然而，与年龄相关的胆碱能系统的减弱可能与这些破坏性的突触前机制协同作用，使该神经递质系统在强烈阻碍注意能力的过程中容易受到寡聚体Aβ的毒性影响。
Substantial evidence suggests that cerebral deposition of the neurotoxic fibrillar form of amyloid precursor protein, β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease (AD). Yet, many aspects of AD pathology including the cognitive symptoms and selective vulnerability of cortically-projecting basal forebrain (BF) cholinergic neurons are not well explained by this hypothesis. Specifically, it is not clear why cognitive decline appears early when the loss of BF cholinergic neurons and plaque deposition are manifested late in AD. Soluble oligomeric forms of Aβ are proposed to appear early in the pathology and to be better predictors of synaptic loss and cognitive deficits. The present study was designed to examine the impact of Aβ oligomers on attentional functions and presynaptic cholinergic transmission in young and aged rats. Chronic intracranial infusions of Aβ oligomers produced subtle decrements in the ability of rats to sustain attentional performance with time on task, irrespective of the age of the animals. However, Aβ oligomers produced robust detrimental effects on performance under conditions of enhanced attentional load in aged animals. In vivo electrochemical recordings show reduced depolarization-evoked cholinergic signals in Aβ-infused aged rats. Moreover, soluble Aβ disrupted the capacity of cholinergic synapses to clear exogenous choline from the extracellular space in both young and aged rats, reflecting impairments in the choline transport process that is critical for acetylcholine (ACh) synthesis and release. Although aging per se reduced the cross-sectional area of BF cholinergic neurons and presynaptic cholinergic proteins in the cortex, attentional performance and ACh release remained unaffected in aged rats infused with the control peptide. Taken together, these data suggest that soluble Aβ may marginally influence attentional functions at young ages primarily by interfering with the choline uptake processes. However, age-related weakening of the cholinergic system may synergistically interact with these disruptive presynaptic mechanisms to make this neurotransmitter system vulnerable to the toxic effects of oligomeric Aβ in robustly impeding attentional capacities.
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影响因子：
6.1
作者：
Hu S;Begum AN;Jones MR;Oh MS;Beech WK;Beech BH;Yang F;Chen P;Ubeda OJ;Kim PC;Davies P;Ma Q;Cole GM;Frautschy SA
通讯作者：
Frautschy SA
影响因子：
3.7
作者：
Dalley, JW;Theobald, DE;Robbins, TW
通讯作者：
Robbins, TW
影响因子：
2.9
作者：
Dodart, JC;Bales, KR;Paul, SM
通讯作者：
Paul, SM
影响因子：
3.7
作者：
Kittelberger KA;Piazza F;Tesco G;Reijmers LG
通讯作者：
Reijmers LG
影响因子：
5.7
作者：
Demeter E;Hernandez-Garcia L;Sarter M;Lustig C
通讯作者：
Lustig C