Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer's disease enabled by positron emission tomography.
We provide the first evidence for the capability of a high-resolution positron emission tomographic (PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor protein transgenic (Tg) mice. After the intravenous administration of N-[11C]methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [11C]PIB for "Pittsburgh Compound-B") with high-specific radioactivity, the Tg mice exhibited high-level retention of radioactivity in amyloid-rich regions. PET investigation for Tg mice over an extended range of ages, including longitudinal assessments, demonstrated age-dependent increase in radioligand binding consistent with progressive amyloid accumulation. Reduction in amyloid levels in the hippocampus of Tg mice was also successfully monitored by multiple PET scans along the time course of anti-amyloid treatment using an antibody against amyloid beta peptide (Abeta). Moreover, PET scans with [18F]fluoroethyl-DAA1106, a radiotracer for activated glia, were conducted for these individuals parallel to amyloid imaging, revealing treatment-induced neuroinflammatory responses, the magnitude of which intimately correlated with the levels of pre-existing amyloid estimated by [11C]PIB. It is also noteworthy that the localization and abundance of [11C]PIB autoradiographic signals were closely associated with those of N-terminally truncated and modified Abeta, AbetaN3-pyroglutamate, in Alzheimer's disease (AD) and Tg mouse brains, implying that the detectability of amyloid by [11C]PIB positron emission tomography is dependent on the accumulation of specific Abeta subtypes. Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.
Maeda
Jun
J
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba 263-8555, Japan.
Ji
Bin
B
Irie
Toshiaki
T
Tomiyama
Takami
T
Maruyama
Masahiro
M
Okauchi
Takashi
T
Staufenbiel
Matthias
M
Iwata
Nobuhisa
N
Ono
Maiko
M
Saido
Takaomi C
TC
Suzuki
Kazutoshi
K
Mori
Hiroshi
H
Higuchi
Makoto
M
Suhara
Tetsuya
T
D000367:Age Factors; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000473:pathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000814:Aniline Compounds; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D013844:Thiazoles
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D000906:Antibodies; D013844:Thiazoles