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The Journal of Neuroscience, October 10, 2007, 27(41):10957-10968; doi:10.1523/JNEUROSCI.0673-07.2007

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Neurobiology of Disease
Longitudinal, Quantitative Assessment of Amyloid, Neuroinflammation, and Anti-Amyloid Treatment in a Living Mouse Model of Alzheimer's Disease Enabled by Positron Emission Tomography

Jun Maeda,¹ Bin Ji,¹ Toshiaki Irie,¹ Takami Tomiyama,² Masahiro Maruyama,¹ Takashi Okauchi,¹ Matthias Staufenbiel,³ Nobuhisa Iwata,⁴ Maiko Ono,¹ Takaomi C. Saido,⁴ Kazutoshi Suzuki,¹ Hiroshi Mori,² Makoto Higuchi,¹ and Tetsuya Suhara¹

¹Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba 263-8555, Japan, ²Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan, ³Novartis Institutes for Biomedical Research–Basel, CH-4002 Basel, Switzerland, and ⁴Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan

Correspondence should be addressed to Dr. Makoto Higuchi, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. Email: mhiguchi{at}nirs.go.jp

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 ß peptide (Aß). 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 Aß, AßN3-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 Aß 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.

Key words: Alzheimer's disease; amyloid; positron emission tomography; transgenic; immunotherapy; neuroinflammation

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Received Feb. 15, 2007; revised Aug. 27, 2007; accepted Aug. 29, 2007.

Correspondence should be addressed to Dr. Makoto Higuchi, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. Email: mhiguchi{at}nirs.go.jp

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