Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice

Abstract

BackgroundDiabetes is the most common metabolic disease with many chronic complications, and cognitive disorders are one of the common complications in patients with diabetes. Previous studies have showed that autophagy played important roles in the progression of metabolic syndrome, diabetes and other diseases. So we investigated whether aged diabetic mice are prone to be associated with the cognitive and affective disorders and whether Beclin-1-mediated autophagy might be involved in thepahological process.MethodsHigh-fat diet/streptozotocin (STZ) injection-induced diabetic C57 mice were adopted in this study. Cognitive disorders were detected by Morris water maze and fear conditional test. Affective disorders were detected by tail suspension test and forced swimming test. Magnetic resonance imaging was applied to observe changes of morphology and metabolism in the brain. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to assess metabolism changes in the brain of aged diabetic mice. Autophagy were evaluated by Beclin- 1, LC3II/I and P62, which were detected by western blot analysis and observed by electron microscopy.Results1. Compared with control group, diabetes mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (all P < 0.05), and increasing tendency of depression (P < 0.05). 2. MRI showed that the majority of elderly diabetic mice were associated with multiple cerebral small vessel disease. Some even showed hippocampal atrophy, ventricular dilatation and leukoaraiosis. 3. FDG-PET-CT discovered that the glucose metabolism in the amygdala and hippocampus was significantly decreased compared with normal aged mice (P < 0.05). 4. Electron microscopy found that, although autophagy bodies was not widespread, and there was no significant difference between the two groups, yet compared with normal aged mice, apparent cell edema, myelinated tow reduction and intracellular lipofuscin augmentation existed in elderly diabetic mice brain. 5. The level of p62 was increased in the STZ-induced diabetic mice hippocampus and striatum, and beclin1 protein expression were significantly decreased in diabetic mice hippocampus compared with normal aged mice (P < 0.05). There was a upward trend of the ratio of LC3II/I in hippocampus, cortex and striatum, but no statistically difference between the two groups.ConclusionCompared with normal aged mice, diabetic aged mice were apt to cerebral small vessel disease and associated with cognitive and affective disorders, which may be related to the significantly reduced glucose metabolism in hippocampus and amygdala. Beclin1 mediated autophagy in hippocampus probably played an important role in cognitive and affective disorders of STZ-induced aged diabetic mice.

Liraglutide improves cognitive impairment via the AMPK and PI3K/Akt signaling pathways in type 2 diabetic rats

“…Autophagy is a highly conserved metabolic process that is present in eukaryotic cells. Autophagy leads to the degradation of cytoplasmic components in lysosomes and has recently attracted considerable attention due to its association with DM-induced cognitive deficits (30). Observed autophagy impairments in the hippocampus of GK rats may result in a reduction in hippocampal cell viability and dendritic spine density (31).…”

“…Autophagy serves an important role in maintaining normal tissue and cellular homeostasis (10). A previous study revealed the crucial role of autophagy in DM, in which autophagy functions to ameliorate or exacerbate DM-induced cognitive dysfunction (9,11). Therefore, regulation of autophagy in the hippocampus may be considered an essential method to ameliorate neuronal damage.…”

A shared comparison of diabetes mellitus and neurodegenerative disorders

“…Impaired autophagy triggers inflammasome activation because antiapoptotic Bcl‐2 family members interact with BECN1, and thus, nuclear factor kabba B (NF‐κB)‐driven antiapoptotic Bcl‐2 proteins repress the BECN1‐dependent autophagy. STZ diabetic mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (all P < 0.05) and the increasing tendency of depression ( P < 0.05) . The affected mice had cerebral microvascular disease involving hippocampal atrophy, ventricular dilatation, and leukoaraiosis, and decreased glucose metabolism in the amygdala and hippocampus ( P < 0.05).…”

Platelet proteolytic machinery assessment in Alzheimer’s disease

“…In more relevance to AD neuropathology, beclin-1 is downregulated in this disease; however, LC3-II can still form without a phagophore on ectopic membrane fragments [21,25] . Beclin-1, an adaptor protein via its partner proteins, can either stimulate or suppress the onset of autophagy [27] . In this study, we observed that beclin-1 levels were elevated in AD patient's platelet.…”