N-TERMINAL HETEROGENEITY OF PARENCHYMAL AND CEREBROVASCULAR A-BETA DEPOSITS

The goals of this study were twofold: to determine whether species dif ferences in A beta N-terminal heterogeneity explain the absence of neu ritic Plaques in the aged dog and aged bear in contrast to the human; and to compare A beta N-terminal isoforms in parenchymal vs cerebrovas cular A beta (CVA) deposits in each of the species, and in individuals with Alzheimer disease (AD) vs nondemented individuals. N-terminal he terogeneity can affect the aggregation, toxicity, and stability of A b eta. The human, polar bear, and dog brain share an identical A beta am ino acid sequence. Tissues were immunostained using affinity-purified polyclonal antibodies specific for the L-aspartate residue of A beta a t position one (A beta N1[D]), D-aspartate at N1 (A beta N1[rD]), and pyroglutamate at N3 (A beta N3[pE]) and p3, a peptide beginning with l eucine at N17 (A beta N17[L]). The results demonstrate that each A bet a N-terminal isoform can be present in diffuse plaques and CVA deposit s in AD brain, nondemented human, and the examined aged animal models. Though each A beta 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 A beta N3(pE) (an isoform that is resistant to degradation by most aminopeptidases) vs A beta N17(L)-x (the potentially nonamyloidogenic p3 fragment) was grea test in the human brain when compared with aged dog or polar bear. Neu ritic plaques in AD brain typically immunostained with antibodies agai nst A beta N1(D) and A beta N3(pE), but not A beta N17(L) or A beta N1 (rD). Neuritic deposits in nondemented individuals with atheroscleroti c and vascular hypertensive changes could be identified with A beta N1 (D), A beta N3(pE), and A beta N1(rD). The presence of A beta N1(rD) i n neuritic plaques in nondemented individuals with atherosclerosis or hypertension, but not in AD, suggests a different evolution of the pla ques in the two conditions. A beta N1(rD) was usually absent in human CVA, except in AD cases with atherosclerotic and vascular hypertensive changes. Together, the results demonstrate that diffuse plaques, neur itic plaques, and CVA deposits are each associated with distinct profi les of A beta N-terminal isoforms.