The Multiple Roles of Autophagy in Neural Function and Diseases

Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes,where proteins,lipids,and organelles are degraded and recycled.According to the way the cytoplasmic components are engulfed,autophagy can be divided into macroautophagy,microautophagy,and chaperone-mediated autophagy.Recently,many studies have found that autophagy plays an important role in neurological diseases,including Alzheimer's disease,Parkinson's disease,Huntington's disease,neuronal excitotoxicity,and cerebral ischemia.Autophagy maintains cell homeostasis in the nervous system via degradation of misfolded proteins,elimination of damaged organelles,and regulation of apoptosis and inflammation.AMPK-mTOR,Beclin 1,TP53,endoplasmic reticulum stress,and other signal pathways are involved in the regulation of autophagy and can be used as potential therapeutic targets for neurological diseases.Here,we discuss the role,functions,and signal pathways of autophagy in neurological diseases,which will shed light on the pathogenic mechanisms of neurological diseases and suggest novel targets for therapies.

Trehalose ameliorates autophagy dysregulation in aged cortex and acts as an exercise mimetic to delay brain aging in elderly mice

Exercise is recognized as an effective strategy to delay brain aging, which is related to the activation of autophagy. Trehalose is a natural compound that can activate autophagy and exert beneficial effects in delaying brain aging. In this study, we investigated whether trehalose may exert neuroprotection similar to those of exercise in delaying age-related cognitive decline. Fifteen-month-old male C57BL/6 mice underwent swim exercise and/or were treated with 2% trehalose for 12 weeks. Trehalose, exercise and the combination of exercise and trehalose intervention improved the learning and memory of aged mice. They also improved the ratio of LC3-II/LC3-I, the protein level of LC3-II, Bnip3L, and Parkin respectively. Additionally, both exercise and trehalose increased the phosphorylation of AMPK. Exercise decreased cortical phosphorylation of m TOR and S6k, whereas trehalose did not change these cortical levels. These data indicated that exercise and trehalose might modulate autophagy through m TOR-dependent or m TOR-independent pathways, respectively. However, a combination of exercise and trehalose did not play a synergistic role in improving cognitive function and modulation of autophagy. Taken together, our findings suggest that trehalose exerts similar effects to those of exercise in delaying age-related cognitive decline and that it may thus represent an exercise mimetic to delay brain aging.

Therapeutic Potential of Naja Naja Atra Venom in A Rat Model of Diabetic Nephropathy

Objective To study the protective effects of naja naja atra venom （NNAV） in a rat model of diabetic nephropathy （DN）. Methods The rat diabetes model was induced by intraperitoneal injection of streptozotocin （STZ）. Thirty-two model rats were randomly divided into one DN group （n=8） and three treatment groups （n=8 each） that received NNAV at doses of 30, 90, or 270 I^g/（ks.day） via oral gavage, another eight rats as normal controls. After 12 weeks, all rats were sacrificed and the changes in serum and urine biological index levels were determined by colorimetric assay. Microalbumin （mALB）, N-acetyl-13- glucosaminidase （NAG） and cystatin C （CysC） concentrations were measured by ELISA. Renal tissues were sliced for pathological and immunohistochemical observations. Results Comparied with the DN group, serum glucose was decreased by 31.04%, total cholesterol 21.96%, triglyceride 23.78%, serum creatinine 19.83%, blood urea nitrogen 31.28%, urinary protein excretion 45.42%, mALB 10.42%, NAG 20.65%, CysC 19.57%, whereas albumin increased by 5.55%, high-density lipoprotein-cholesterol 59.09%, creatinine clearance 19.05% in the treatment group by NNAV administration at dose of 90 μg/（kg-day）. NNAV also reduced the levels of malondialdehyde in serum （22.56%） and kidney tissue （9.79%）, and increased superoxide dismutase concentration in serum （15%） and decreased it in renal tissue （8.85%）. In addition, under light microscopy kidney structure was improved and glomerular hypertrophy decreased by 8.29%. As shown by immunohistochemistry, NNAV inhibited transforming growth factorl by 6.70% and nuclear actor-KB by 5.15%.

Endogenous level of TIGAR in brain is associated with vulnerability of neurons to ischemic injury

In previous studies,we showed that TP53-induced glycolysis and apoptosis regulator（TIGAR） protects neurons against ischemic brain injury.In the present study,we investigated the developmental changes of TIGAR level in mouse brain and the correlation of TIGAR expression with the vulnerability of neurons to ischemic injury.We found that the TIGAR level was high in the embryonic stage,dropped at birth,partially recovered in the early postnatal period,and then continued to decline to a lower level in early adult and aged mice.The TIGAR expression was higher after ischemia/reperfusion in mouse brain 8and 12 weeks after birth.Four-week-old mice had smaller infarct volumes,lower neurological scores,and lower mortality rates after ischemia than 8- and12-week-old mice.TIGAR expression also increased in response to oxygen glucose deprivation（OGD）/reoxygenation insult or H_2O_2 treatment in cultured primary neurons from different embryonic stages（E16 and E20）.The neurons cultured from the early embryonic period had a greater resistance to OGD and oxidative insult.Higher TIGAR levels correlated with higher pentose phosphate pathway activity and less oxidative stress.Older mice and more mature neurons had more severe DNA and mitochondrial damage than younger mice and less mature neurons in response to ischemia/reperfusion or OGD/reoxygenation insult.Supplementation of cultured neurons with nicotinamide adenine dinuclectide phosphate（NADPH） significantly reduced ischemic injury.These results suggest that TIGAR expression changes during development and its expression level may be correlated with the vulnerability of neurons to ischemic injury.

Neuronal autophagy in cerebral ischemia

Autophagy has evolved as a conserved process for the bulk degradation and recycling of cytosolic components, such as long-lived proteins and organelles. In neurons, autophagy is important for homeostasis and protein quality control and is maintained at relatively low levels under normal conditions, while it is upregulated in response to pathophysiological conditions, such as cerebral ischemic injury. However, the role of autophagy is more complex. It depends on age or brain maturity, region, severity of insult, and the stage of ischemia. Whether autophagy plays a beneficial or a detrimental role in cerebral ischemia depends on various pathological conditions. In this review, we elucidate the role of neuronal autophagy in cerebral ischemia.