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In Vivo Positron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders
Open accessAbstract
Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [11 C]AC-5216 and [18 F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11 C]Pittsburgh Compound-B, to plaques. In these animals, [11 C]AC-5216 yielded better TSPO contrasts than [18 F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.
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“TPSO signal has been shown to increase with microglia activation in tauopathies including AD, PSP, PiD, and FTDP-17 [111–113] as well as several other neurodegenerative diseases and injury models such as other frontotemporal dementias (FTDs), Parkinson’s disease, stroke and TBI [114].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [111]
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“Importantly, TPSO signaling preceded thioflavin-S-positive tangles and MRI-measureable regional atrophy in the mice implying TPSO PET may be more adept at detecting neuroinflammation induced by tau aggregation [111].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [111]
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Metadata
- Authors
- Maeda, J., Zhang, M.-R., Okauchi, T., Ji, B., Ono, M., Hattori, S., Kumata, K., Iwata, N., Saido, T. C., Trojanowski, J. Q., Lee, V. M.-Y., Staufenbiel, M., Tomiyama, T., Mori, H., Fukumura, T., Suhara, T., & Higuchi, M.
- Affiliations
- National Institute of Radiological Sciences (JP)
- RIKEN Center for Brain Science (JP)
- University of Pennsylvania (US)
- Novartis (Switzerland) (CH)
- Osaka City University (JP)
- Corresponding author
- Higuchi, Makoto
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-03-23
- Volume
- 31
- Issue
- 12
- Pages
- 4720-4730
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3251921
- OpenAlex
- W2160881303
- Cited by
- 136
- References
- 53
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 9 · 2022: 4 · 2021: 14 · 2020: 14 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 10 · 2015: 12 · 2014: 17 · 2013: 14 · 2012: 9
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health (AG 10 124, AG 17586)
- Japan Society for the Promotion of Science (20790047, 23390235, 20023036, 22790835)
- National Institute on Aging (P30AG010124, P01AG017586, AG17586, AG-10124)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, tauopathy, translocator protein (TSPO), microglial activation, amyloid plaques, tau fibrils, TSPO PET imaging, Pittsburgh compound B, intraneuronal amyloid-beta, neurodegeneration biomarkers, neuroinflammation
- MeSH terms
- Acetamides, Alzheimer Disease, Aniline Compounds, Animals, Autoradiography, Brain, Humans, Immunohistochemistry, Isotope Labeling, Magnetic Resonance Imaging, Mice, Inbred C57BL, Neuritis, Neuroglia, Purines, Supranuclear Palsy, Progressive, Thiazoles, Amyloid beta-Protein Precursor, tau Proteins, Receptors, GABA, Radiopharmaceuticals, Pick Disease of the Brain, Positron-Emission Tomography, Mice, Plaque, Amyloid
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