Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model

NEUROBIOLOGY OF DISEASE

卷:137

Article

Imamura, Tomohiro¹  Yanagihara, Yuki T.¹  Ohyagi, Yasumasa²  Nakamura, Norimichi¹  Iinuma, Kyoko M.¹  Yamasaki, Ryo¹  Asai, Hirohide¹  Maeda, Masahiro³  Murakami, Kazuma⁴  Irie, Kazuhiro⁴  Kira, Jun-ichi¹ 

[1] Kyushu Univ, Neurol Inst, Grad Sch Med Sci, Dept Neurol,Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan

[2] Ehime Univ, Dept Neurol & Geriatr Med, Grad Sch Med, 454 Shitsukawa, Toon, Ehime 7910295, Japan

[3] Immunobiol Labs Co Ltd, 1091-1 Naka, Fujioka, Gunma 3700005, Japan

[4] Kyoto Univ, Div Food Sci & Biotechnol, Grad Sch Agr, Sakyo Ku, Kitashirakawa Oiwakecho, Kyoto 6068502, Japan

关键词: Alzheimer's disease;    Animal model;    3xTg-AD mouse;    Toxic amyloid beta conformer;    Insulin deficiency;    Insulin resistance;    Tau oligomer;    Insulin signaling;    Microglia;   

DOI  :  10.1016/j.nbd.2020.104739

来源: Elsevier

【 摘 要 】

The toxic conformer of amyloid beta-protein (A beta) ending at 42 (A beta 42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic A beta 42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic A beta 42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic A beta 42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PSI (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total A beta 42 levels and the ratio of toxic A beta 42 conformer/total A1342 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic A beta 42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic A beta 42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic A beta 42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = - 0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic A beta 42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3 beta measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Ibal-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic A beta 42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.