In vivo detection of amyloid plaques in a mouse model of Alzheimer's disease.
Strategies for treating Alzheimer's disease (AD) include therapies designed to decrease senile plaque (SP) formation and/or promote clearance of SPs, but clinical trials of these treatments are limited by the lack of effective methods to monitor changes in plaque burden in the brains of living AD patients. However, because SPs are extracellular deposits of amyloid-beta peptides (Abeta), it may be possible to eventually develop radioligands that cross the blood-brain barrier (BBB) and label SPs so they can be visualized by current imaging methods. As a first step toward the generation of such a radioligand, we developed a probe, [(trans,trans)-1-bromo-2, 5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB)], and we report here that BSB has the following properties essential for a probe that can detect SPs in vivo. First, BSB sensitively labels SPs in AD brain sections. Second, BSB permeates living cells in culture and binds specifically to intracellular Abeta aggregates. Third, after intracerebral injection in living transgenic mouse models of AD amyloidosis, BSB labels SPs composed of human Abeta with high sensitivity and specificity. Fourth, BSB crosses the BBB and labels numerous AD-like SPs throughout the brain of the transgenic mice after i.v. injection. Thus, we conclude that BSB is an appropriate starting point for future efforts to generate an antemortem diagnostic for AD.
Skovronsky
D M
DM
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Zhang
B
B
Kung
M P
MP
Kung
H F
HF
Trojanowski
J Q
JQ
Lee
V M
VM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015335:Molecular Probes; D011869:Radioligand Assay; D012680:Sensitivity and Specificity; D013194:Staining and Labeling
D016229:Amyloid beta-Peptides; D015335:Molecular Probes