Biol Pharm Bull. 2015;38(4):601-610.

Effect of High Glucose Levels on Amyloid β Production in Retinas of Spontaneous Diabetes Mellitus Otsuka Long-Evans Tokushima Fatty Rats.

 

Noriaki Nagai1*, Yoshimasa Ito1, Tadatoshi Tanino2

1Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan

2Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-Cho, Tokushima, Tokushima 770-8514, Japan

 

ABSTRACT

The accumulation of amyloid β1-42 peptide (Aβ1-42) in retina is implicated in the development of retinal ganglion cell apoptosis and diabetic retinopathy. In this study we demonstrate that spontaneous diabetes mellitus Otsuka Long-Evans Tokushima Fatty (OLETF) rats can be used as an animal model in studies to identify the expression of Aβ in diabetic retinas. In addition, we investigated the relation between glucose level and Aβ production in the retinas of OLETF rats. In the retinas of Long-Evans Tokushima Otsuka (LETO) rats used as normal controls and OLETF rats, no expression of neprilysin (NEP), which degrades Aβ, was detected, and the expression levels of genes associated with Aβ production (amyloid precursor protein, β site APP cleaving enzyme, and presenilin) and Aβ1-42 levels in the retinas of 60-week-old OLETF rats with diabetes mellitus were significantly higher than in 60-week-old LETO rat retinas. Furthermore, the increase in the expression levels of genes associated with Aβ production was enhanced by administration of glucose (3.0 g/kg; OGT test), and close relations between the retinal Aβ1-42 level and plasma blood glucose and HbA1c were observed. In conclusion, we have found that Aβ accumulates easily in the retinas of LETO and OLETF rats due to the absence of NEP. In addition, we determined that the accumulation of Aβ1-42 in the retinas of OLETF rats is promoted by high plasma glucose levels. Therefore OLETF rats may be a suitable model for studies to identify the expression of Aβ in diabetic retinas.

Keywords: amyloid β (Aβ), retina, diabetes mellitus, glucose, Otsuka Long-Evans Tokushima Fatty (OLETF) rat.

PMID: 25832640

 

Highlights

  In the retinas of LETO rats used as normal controls and OLETF rats, no expression of neprilysin, which degrades Aβ, was detected.

  The expression levels of genes associated with Aβ production and Aβ1-42 levels in the retinas of 60-week-old OLETF rats were significantly higher than in 60-week-old LETO rat retinas.

  A close relations between the retinal Aβ1-42 level and plasma blood glucose and HbA1c were observed.

  The increase in the expression levels of genes associated with Aβ production was enhanced by administration of glucose (OGT test).

  It is possible that The chronically high blood glucose levels elevate the expressions of genes responsible for Aβ production, resulting in the accumulation of soluble and insoluble Aβ1-42 in the retinas of 60-week-old OLETF rats.

  The OLETF rats may provide a suitable animal model for studies related to Aβ in the retinas of patients with diabetes mellitus.

 

 

NN FIG1-1

Figure 1. Changes in the Expression of APP, ADAM10, BACE1, PS1 and PS2 mRNAs Levels in 60-Week-Old LETO and OLETF Rats in Response to an Oral Glucose Tolerance Test.

A, Changes in glucose levels in the LETO and OLETF rats after the oral administration of glucose (3.0 g/kg). Open circles, LETO rat; closed circles, OLETF rat. The data are presented as means ± S.E. of 6 independent rats. *1P < 0.05 vs. LETO rat. B-F, Expression of APP (B), ADAM10 (C), BACE1 (D), PS1 (E) and PS2 (F) mRNAs in the retinas of LETO and OLETF rats at 180 min after the oral administration of glucose (3.0 g/kg). Open columns, LETO or OLETF rat at 180 min after the oral administration of purified water (PW); Closed columns, LETO or OLETF rat at 180 min after the oral administration of glucose (Glucose). The data are presented as means ± S.E. of 6 independent rats. *2P < 0.05 vs. PW-administered LETO rat. *3P < 0.05 vs. PW-administered OLETF rat.

 

 

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