Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology.
We previously showed that microglial keratan sulfate (KS) was induced in amyotrophic lateral sclerosis. However, the functional roles of the glycan and its synthetic enzyme in neurodegenerative diseases, such as Alzheimer's disease (AD), a progressive disorder, are unclear. In our study, KS modified with sialic acids having a molecular mass of 125-220 kDa and the carbohydrate sulfotransferase GlcNAc6ST1 were up-regulated in the brains of two transgenic mouse models (J20 and Tg2576) and the brains of patients with AD. GlcNAc6ST1-deficient J20 (J20/GlcNAc6ST1-/-) mice demonstrated a complete absence of the microglial sialylated KS. J20/GlcNAc6ST1-/-primary microglia showed an increased level of amyloid-β phagocytosis and were hyperresponsive to interleukin 4, a potent antiinflammatory cytokine. Moreover, J20/GlcNAc6ST1-/-mice manifested reduced cerebral amyloid-β deposition. GlcNAc6ST1-synthesizing sialylated KS thus modulates AD pathology. Inhibition of KS synthesis by targeting GlcNAc6ST1 may therefore be beneficial for controlling AD pathogenesis.
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Zui
Z
Zhang
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Yoshiko
Y
Takeda-Uchimura
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Tahmina
T
Foyez
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Shiori
S
Ohtake-Niimi
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Narentuya
Choju Medical Institute, Fukushimura Hospital, Toyohashi, 441-8124, Japan.|Department of Community-Based Medicine, Nagoya City University Graduate School of Medicine, Nagoya, 467-8601, Japan.
Hiroyasu
H
Akatsu
Department of Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan.
Kazuchika
K
Nishitsuji
Department of Biochemistry, Nagoya City University Graduate School of Medicine, Nagoya, 467-8601, Japan.|Department of Alzheimer's Disease Research, National Center for Geriatrics and Gerontology, Obu, 474-8511, Japan.
Makoto
M
Michikawa
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
Tony
T
Wyss-Coray
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Kenji
K
Kadomatsu
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; arumihcu@med.nagoya-u.ac.jp.|Department of Alzheimer's Disease Research, National Center for Geriatrics and Gerontology, Obu, 474-8511, Japan.
Kenji
K
Uchimura
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007632:Keratan Sulfate / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D010587:Phagocytosis; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011134:Polysaccharides / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism*; D000097811:Carbohydrate Sulfotransferases
D016564:Amyloid beta-Protein Precursor; D007632:Keratan Sulfate; D019158:N-Acetylneuraminic Acid; D011134:Polysaccharides; D015238:Sulfotransferases; D000097811:Carbohydrate Sulfotransferases
Alzheimer's disease; carbohydrate-recognizing receptors; microglia; sialic acid; sulfotransferase