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- Kumar, Amit, et al.
(författare)
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Astroglial tracer BU99008 detects multiple binding sites in Alzheimer's disease brain
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:10, s. 5833-5847
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Tidskriftsartikel (refereegranskat)abstract
- With reactive astrogliosis being established as one of the hallmarks of Alzheimer’s disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.
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| 2. |
- Lemoine, Laetitia, et al.
(författare)
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Amyloid, tau, and astrocyte pathology in autosomal-dominant Alzheimer's disease variants : A beta PParc and PSEN1DE9
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:10, s. 5609-5619
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using(11)C-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(3)H-PiB,H-3-MK6240-H-3-THK5117, and(3)H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in twoA beta PParcmutation carriers, onePSEN1 Delta E9mutation 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 inA beta PParc. A high binding was observed inPSEN1 Delta E9and in sAD tissues but with different binding patterns. Comparable(3)H-THK5117 and(3)H-deprenyl brain homogenate binding was observed forA beta PParc,PSEN1 Delta E9, and sAD, respectively. Some differences were observed between(3)H-MK6240 and(3)H-THK5117 in ADAD. A positive correlation between(3)H-deprenyl and(3)H-THK5117 binding was observed inA beta PParc, while no such correlation was found inPSEN1 Delta E9and 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 theA beta PParccases, high regional tau and astrocyte binding was observed. The lack of correlation between(3)H-deprenyl and(3)H-THK5117 binding inPSEN1 Delta E9and sAD in contrast of the positive correlation observed in theA beta PParccases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.
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