Abstract
Autosomal-dominant Alzheimer’s disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using 11C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer’s disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with 3H-PiB, 3H-MK6240-3H-THK5117, and 3H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable 3H-THK5117 and 3H-deprenyl brain homogenate binding was observed for AβPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between 3H-MK6240 and 3H-THK5117 in ADAD. A positive correlation between 3H-deprenyl and 3H-THK5117 binding was observed in AβPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AβPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between 3H-deprenyl and 3H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AβPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.In a small percentage of patients, Alzheimer’s disease (AD) is characterized by an early onset due to a mutation in one of three identified genes: amyloid-beta precursor protein (AβPP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2)
The regional binding of 3H-Pittsburgh compound B (PIB) on large frozen brain sections of the two AβPParc mutation carriers, the PSEN1DE9 mutation carrier and one sporadic Alzheimer’s disease (sAD) case is presented in Fig. 1. 3HPIB binding was very low in the whole brain hemisphere sections of the two AβPParc brains in comparison to the sAD brain
The aim of the study was to compare the neuropathological features of the AβPParc and PSEN1DE9 mutations with those of sAD using in vitro binding studies of autopsied brain tissue with PET ligands, in order to be able to understand the relationships between the different hallmarks of AD pathology
Summary
E693G) is pathologically characterized by the presence of ring-shaped amyloid plaques without amyloid core [5] Those plaques are Congo red negative but amyloid beta 42-positive on the ring as observed using amyloid beta 1–42 antibodies [1, 6]. In 2012 compared both the amyloid plaques structure and the accumulations of N- and C-truncated Aβ in AβPParc, PSEN1DE9 and sAD, and they could observe differences in length accumulation of N- and C-truncated Aβ40 and 42 between the two mutation and sAD in parenchymal plaques as well as in cerebral amyloid angyopathy [9]. The in vivo PET binding of 11C-Pittsburgh compound B (PiB) is low in both symptomatic and nonsymptomatic AβPParc carriers in comparison to patients with sAD while levels of amyloid beta 42, total tau and P-tau in the cerebrospinal fluid and cerebral metabolism as measured by 18Ffluorodeoxyglucose (FDG) PET are comparable with sAD [6, 10, 11]
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