N-terminal heterogeneity of parenchymal and cerebrovascular aβ deposits

Abstract

The goals of this study were twofold: to determine whether species differences in Aβ N-terminal heterogeneity explain the absence of neuritic plaques in the aged dog and aged bear in contrast to the human; and to compare Aβ N-terminal isoforms in parenchymal vs cerebrovascular Aβ (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 Aβ. The human, polar bear, and dog brain share an identical Aβ amino acid sequence. Tissues were immunostained using affinity-purified polyclonal antibodies specific for the L-aspartate residue of Aβ at position one (AβN1[D]), D-aspartate at N1 (AβN1[rD]), and pyroglutamate at N3 (AβN3[pE]) and p3, a peptide beginning with leucine at N17 (AβN17[L]). The results demonstrate that each Aβ 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 Aβ 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 AβN3(pE) (an isoform that is resistant to degradation by most aminopeptidases) vs AβN17(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 AβN1(D) and AβN3(pE), but not AβN17(L) or AβN1(rD). Neuritic deposits in nondemented individuals with atherosclerotic and vascular hypertensive changes could be identified with AβN1(D), AβN3(pE), and AβN1(rD). The presence of AβN1(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. AβN1(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 Aβ N-terminal isoforms.