Beta-amyloid-related peptides inhibit potassium-evoked acetylcholine release from rat hippocampal slices
Beta-amyloid-related peptides inhibit potassium-evoked acetylcholine release from rat hippocampal slices
复制标题
β-淀粉样蛋白相关肽抑制大鼠海马切片钾诱发的乙酰胆碱释放
DOI：
10.1523/jneurosci.16-03-01034.1996
复制
发表时间：
1996
影响因子：
6.4
通讯作者：
Remi Quirionll
中科院分区：
文献类型：
--
作者：
Satyabrata Kar;David Seto;Pierrette Gaudreau;Remi Quirionll
4 kDa β-淀粉样蛋白（A β）是阿尔茨海默病（AD）中脑和脑血管斑块的主要成分，来源于较大的膜结合前体A β前体蛋白（APP）的蛋白水解裂解。直到最近，人们还认为异常AD特异性蛋白水解产生A β肽，随后可能引发和/或促成病理级联反应，导致斑块形成和选定神经元群体（包括向海马和新皮质提供主要输入的基底前脑胆碱能神经元）的损失。然而，最近在正常个体的血浆和CSF中以及在培养的脑细胞的条件培养基中检测到可溶性A β片段，表明A β相关肽在正常脑功能中的作用。考虑到已报道的A β的毒性特性和AD中基底前脑胆碱能神经元的优先脆弱性，我们研究了A β相关肽对大鼠脑片内源性乙酰胆碱（ACh）释放的可能影响。A β 1-28以浓度依赖性方式（10（-12）-10（-8）M）有效抑制K（+）诱发的海马脑片ACh释放。ACh释放的抑制是完全可逆的，并且使用其他A β相关肽如A β 1-42、A β 1-40和A β 25-35观察到，但不使用乱序、反向或所有D-异构体A β肽序列，表明A β对ACh释放的影响是通过立体选择性机制介导的。河豚毒素（10 μ M）不能改变A β 1-28对ACh释放的作用，这表明缺乏电压依赖性Na+通道的参与.除海马结构外，A β对K（+）诱发的ACh释放的抑制作用也见于额叶皮质，而在纹状体无此作用。综上所述，我们的研究结果表明，APP衍生的A β相关肽可以通过作用于胆碱能末梢来有效地调节ACh的释放。此外，选择胆碱能神经元群体对A β敏感的证据表明，A β的沉积和AD中某些胆碱能投射的优先脆弱性之间存在潜在的机制联系。
The 4 kDa beta-amyloid (A beta) protein, a major component of cerebral and cerebrovascular plaques in Alzheimer's disease (AD), is derived from the proteolytic cleavage of a larger, membrane-bound precursor, the A beta precursor protein (APP). Until recently, it was assumed that an aberrant AD-specific proteolysis generated A beta peptides, which subsequently could initiate and/or contribute to the pathological cascade leading to plaque formation and losses of selected neuronal populations, including basal forebrain cholinergic neurons that provide major inputs to the hippocampus and neocortex. However, the recent detection of soluble A beta fragments in the plasma and CSF of normal individuals, as well as in the conditioned media of cultured brain cells, suggests a role for A beta-related peptides in normal brain functions. Taking into consideration the reported toxic properties of A beta and the preferential vulnerability of basal forebrain cholinergic neurons in AD, we investigated the possible effects of A beta-related peptides on the release of endogenous acetylcholine (ACh) from rat brain slices. A beta 1–28, in a concentration-dependent manner (10(-12)– 10(-8) M), potently inhibited K(+)-evoked ACh release from hippocampal slices. The inhibition of ACh release was fully reversible and was observed using other A beta-related peptides such as A beta 1–42, A beta 1–40, and A beta 25–35, but not with the scrambled, reverse, or all D-isomer A beta-peptide sequences, indicating that the effect of A beta on ACh release is mediated via a stereoselective mechanism. Tetrodotoxin (10 microM) failed to alter the effect of A beta 1–28 on ACh release, which suggests the lack of involvement of voltage- dependent Na+ channels. Except for the hippocampal formation, the inhibitory effect of A beta on K(+)-evoked ACh release also was observed in the frontal cortex but not in the striatum. Taken together, our results demonstrate that APP-derived A beta-related peptides can regulate the release of ACh potently by acting on cholinergic terminals. Additionally, the evidence that selected cholinergic neuronal populations are sensitive to A beta suggests a potential mechanistic link between the deposition of A beta and the preferential vulnerability of certain cholinergic projections in AD.
影响因子：
56.9
作者：
YANKNER, BA;DUFFY, LK;KIRSCHNER, DA
通讯作者：
KIRSCHNER, DA
DOI：
10.1073/pnas.89.21.10075
发表时间：
1992-11-01
影响因子：
11.1
作者：
BUXBAUM, JD;OISHI, M;GREENGARD, P
通讯作者：
GREENGARD, P