Tekirian T L, Saido T C, Markesbery W R, Russell M J, Wekstein D R, Patel E, Geddes J W
Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
J Neuropathol Exp Neurol. 1998 Jan;57(1):76-94. doi: 10.1097/00005072-199801000-00009.
The goals of this study were twofold: to determine whether species differences in Abeta N-terminal heterogeneity explain the absence of neuritic plaques in the aged dog and aged bear in contrast to the human; and to compare Abeta N-terminal isoforms in parenchymal vs cerebrovascular Abeta (CVA) deposits in each of the species, and in individuals with Alzheimer disease (AD) vs nondemented individuals. N-terminal heterogeneity can affect the aggregation, toxicity, and stability of Abeta. The human, polar bear, and dog brain share an identical Abeta amino acid sequence. Tissues were immunostained using affinity-purified polyclonal antibodies specific for the L-aspartate residue of Abeta at position one (AbetaN1[D]), D-aspartate at N1 (AbetaN1[rD]), and pyroglutamate at N3 (AbetaN3[pE]) and p3, a peptide beginning with leucine at N17 (AbetaN17[L]). The results demonstrate that each Abeta N-terminal isoform can be present in diffuse plaques and CVA deposits in AD brain, nondemented human, and the examined aged animal models. Though each Abeta N-terminal isoform was present in diffuse plaques, the average amyloid burden of each isoform was highest in AD vs polar bear and dog (beagle) brain. Moreover, the ratio of AbetaN3(pE) (an isoform that is resistant to degradation by most aminopeptidases) vs AbetaN17(L)-x (the potentially nonamyloidogenic p3 fragment) was greatest in the human brain when compared with aged dog or polar bear. Neuritic plaques in AD brain typically immunostained with antibodies against AbetaN1(D) and AbetaN3(pE), but not AbetaN17(L) or AbetaN1(rD). Neuritic deposits in nondemented individuals with atherosclerotic and vascular hypertensive changes could be identified with AbetaN1(D), AbetaN3(pE), and AbetaN1(rD). The presence of AbetaN1(rD) in neuritic plaques in nondemented individuals with atherosclerosis or hypertension, but not in AD, suggests a different evolution of the plaques in the two conditions. AbetaN1(rD) was usually absent in human CVA, except in AD cases with atherosclerotic and vascular hypertensive changes. Together, the results demonstrate that diffuse plaques, neuritic plaques, and CVA deposits are each associated with distinct profiles of Abeta N-terminal isoforms.
确定β淀粉样蛋白（Aβ）N端异质性的物种差异是否解释了与人类相比，老年犬和老年熊中不存在神经炎性斑块；并比较每个物种的实质与脑血管Aβ（CVA）沉积物中以及患有阿尔茨海默病（AD）的个体与非痴呆个体中的Aβ N端亚型。N端异质性可影响Aβ的聚集、毒性和稳定性。人类、北极熊和犬脑具有相同的Aβ氨基酸序列。使用针对Aβ第1位L-天冬氨酸残基（AβN1[D]）、N1位D-天冬氨酸（AβN1[rD]）、N3位焦谷氨酸（AβN3[pE]）以及以N17位亮氨酸开头的肽p3（AβN17[L]）的亲和纯化多克隆抗体对组织进行免疫染色。结果表明，每种Aβ N端亚型均可存在于AD脑、非痴呆人类以及所检测的老年动物模型的弥漫性斑块和CVA沉积物中。尽管每种Aβ N端亚型均存在于弥漫性斑块中，但与北极熊和犬（比格犬）脑相比，AD中每种亚型的平均淀粉样蛋白负荷最高。此外，与老年犬或北极熊相比，人脑中AβN3（pE）（一种对大多数氨肽酶降解具有抗性的亚型）与AβN17（L）-x（潜在的非淀粉样生成性p3片段）的比率最大。AD脑中的神经炎性斑块通常用针对AβN1（D）和AβN3（pE）的抗体进行免疫染色，但不用针对AβN17（L）或AβN1（rD）的抗体。患有动脉粥样硬化和血管性高血压改变的非痴呆个体中的神经炎性沉积物可用AβN1（D）、AβN3（pE）和AβN1（rD）识别。患有动脉粥样硬化或高血压的非痴呆个体的神经炎性斑块中存在AβN1（rD），而AD中不存在，这表明两种情况下斑块的演变不同。除了患有动脉粥样硬化和血管性高血压改变的AD病例外，人CVA中通常不存在AβN1（rD）。总之，结果表明弥漫性斑块、神经炎性斑块和CVA沉积物均与Aβ N端亚型的不同特征相关。
