Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5-(5M) and 10-(10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid ß1-42 (sAß1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAß1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.

Is galactose a hormetic sugar? Evidence from rat hippocampal redox regulatory network

“…This concept is supported by findings from our group as long-term oral galactose treatment both prevents 8 and ameliorates 38 cognitive deficits in the rat model of sporadic Alzheimer’s disease induced by intracerebroventricular administration of streptozotocin (STZ-icv) characterized by disrupted insulin signaling in the brain 91 . Furthermore, oral galactose has been shown to normalize brain glucose metabolism both in STZ-icv 38 and in the Tg2576 model of Alzheimer’s disease 42 .…”

“…Because current evidence speaks in favor of galactose metabolic capacity of the cell as a critical factor for the determination of pathophysiological consequences of increased galactose availability, and that both factors exert significant influence over local galactose availability in different tissues, a proper understanding of these concepts is indispensable for interpretation of the results of animal studies on galactose. A plethora of studies have shown the detrimental effects of parenteral galactose 18, 92 , while oral galactose administration seems to exert beneficial effects at least in different animal models of Alzheimer’s disease 8, 38, 42 . Different explanations have been proposed considering these findings.…”

“…CTR received no galactose treatment and was used as baseline control and groups GAL 0.5h, GAL 1h, and GAL 2h received galactose solution by orogastric gavage (1 ml of 200 mg/kg galactose dissolved in water) and were sacrificed either 30, 60, or 120 minutes after the treatment respectively. Treatment dose was chosen based on our previous research 8, 38, 42 . Time-points were chosen based on previous findings that galactose plasma concentration is increased 15 minutes after both peroral and intraperitoneal treatment in both STZ-icv 38 and control animals [unpublished data], and that this increment is resolved 30 minutes after peroral administration of 200 mg/kg solution (see Fig 2B) indicating that at approximately this time point galactose metabolism in target tissues is taking place.…”

“…The hypothesis that the protective effects of galactose are inseparable from its stimulatory effect on ROS formation remains to be placed under scientific scrutiny. Nevertheless, if this hypothesis proves to be correct, its A plethora of studies have shown the detrimental effects of parenteral galactose 18,92 , while oral galactose administration seems to exert beneficial effects at least in different animal models of Alzheimer's disease 8,38,42 .…”

Divergent effect of central incretin receptors inhibition in a rat model of sporadic Alzheimer’s disease

“…Two experiments with 4 groups each were conducted with the same procedure. Three-month-old male Wistar rats were subjected to general anesthesia (ketamine 70 mg/kg; 7 mg/kg xylazine), followed by intracerebroventricular injection of STZ (3 mg/kg, dissolved in 0.05 M citrate buffer, pH 4.5, bilaterally 2 µL/ventricle, split into two doses administered on day 1 and 3), according to the procedure first described by Noble et al (Noble et al, 1967) and used in our previous experiments (Babic Perhoc et al, 2019;Grünblatt et al, 2007;Knezovic et al, 2015;Osmanovic Barilar et al, 2015;Salkovic-Petrisic et al, 2014). Control (CTR) animals were given an equal volume of vehicle (0.05M citrate buffer, pH 4.5) icv by the same procedure on days 1 and 3 (Fig 1).…”