title: In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer's disease and related disorders.
abstract: 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.
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba 263-8555, Japan.
authors: Jun
authors: J
authors: Maeda
authors: Ming-Rong
authors: MR
authors: Zhang
authors: Takashi
authors: T
authors: Okauchi
authors: Bin
authors: B
authors: Ji
authors: Maiko
authors: M
authors: Ono
authors: Satoko
authors: S
authors: Hattori
authors: Katsushi
authors: K
authors: Kumata
authors: Nobuhisa
authors: N
authors: Iwata
authors: Takaomi C
authors: TC
authors: Saido
authors: John Q
authors: JQ
authors: Trojanowski
authors: Virginia M-Y
authors: VM
authors: Lee
authors: Matthias
authors: M
authors: Staufenbiel
authors: Takami
authors: T
authors: Tomiyama
authors: Hiroshi
authors: H
authors: Mori
authors: Toshimitsu
authors: T
authors: Fukumura
authors: Tetsuya
authors: T
authors: Suhara
authors: Makoto
authors: M
authors: Higuchi
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000814:Aniline Compounds; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007553:Isotope Labeling / Q000379:methods; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009443:Neuritis / Q000473:pathology; D009457:Neuroglia / Q000000981:diagnostic imaging* / Q000473:pathology*; D020774:Pick Disease of the Brain / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology; D049268:Positron-Emission Tomography; D011687:Purines / Q000138:chemical synthesis; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D018079:Receptors, GABA / Q000378:metabolism; D013494:Supranuclear Palsy, Progressive / Q000473:pathology; D013844:Thiazoles; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000081:Acetamides; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; C463819:Bzrp protein, mouse; C475621:N-(5-fluoro-2-phenoxyphenyl)-N-(2-fluoroethyl-5-methoxybenzyl)acetamide; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011687:Purines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; D013844:Thiazoles; D016875:tau Proteins