Tl. Tekirian et al., N-TERMINAL HETEROGENEITY OF PARENCHYMAL AND CEREBROVASCULAR A-BETA DEPOSITS, Journal of neuropathology and experimental neurology, 57(1), 1998, pp. 76-94
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.