Jiong Ding

Impairments of astrocytes are involved in the D-galactose-induced brain aging

Astrocyte dysfunction is implicated in course of various age-related neurodegenerative diseases. Chronic injection of d-galactose can cause a progressive deterioration in learning and memory capacity and serve as an animal model of aging. To investigate the involvement of astrocytes in this model, oxidative stress biomarkers, biochemical and pathological changes of astrocytes were examined in the hippocampus of the rats with six weeks of d-galactose injection. d-galactose-injected rats displayed impaired antioxidant systems, an increase in nitric oxide levels, and a decrease in reduced glutathione levels. Consistently, western blotting and immunostaining of glial fibrillary acidic protein showed extensive activation of astrocytes. Double-immunofluorescent staining further showed activated astrocytes highly expressed inducible nitric oxide synthase. Electron microscopy demonstrated the degeneration of astrocytes, especially in the aggregated area of synapse and brain microvessels. These findings indicate that impairments of astrocytes are involved in oxidative stress-induced brain aging by chronic injection of d-galactose.

Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice

To investigate the role of astroglial water channel aquaporin-4 (AQP4) in maintaining blood–brain barrier integrity, structure and permeability of the brain microvessels were investigated in adult AQP4 knockout mice. Altered ultrastructure of brain microvessels, including open tight junctions and swollen perivascular astrocytic endfeet, were frequently observed in the AQP4 null mice. Likewise, AQP4 deficiency significantly downregulated expression of glial fibrillary acidic protein in perivascular processes of astrocytes. Furthermore, the horseradish peroxidase analysis demonstrated hyperpermeability of the blood–brain barrier in AQP4 knockout mice. These findings provide direct evidence that AQP4 is essential for the maintenance of blood–brain barrier integrity.

Chronic systemic injection of D-galactose impairs the septohippocampal cholinergic system in rats.

Accumulated evidence indicates chronic systemic injection of D-galactose mimics aging progress induced by oxidative stress. We addressed whether memory impairment in this model was associated with the cholinergic septohippocampal degeneration. Rats injected with D-galactose for 6 weeks showed impairment of spatial learning and memory as measured by the water maze test. Correspondingly, anti-choline acetyltransferase immunohistochemistry demonstrated a severe loss of cholinergic terminals in the hippocampus accompanied by a mild cholinergic neuronal atrophy and loss in the medial septum and the nucleus of the vertical limb of the diagonal band of Broca. A major synaptic degeneration in the hippocampus was confirmed by ultrastructural analysis. These findings provide neuropathological evidence for rodents with chronic injection of D-galactose as a promising model for brain aging and age-related neurodegeneration.

Aquaporin-4 mediates astrocyte response to β-amyloid.

It has been demonstrated that the water channel protein aquaporin-4 (AQP4) plays an important role in astrocyte plasticity in response to a variety of injuries or stimuli. However, the potential role of AQP4 in astrocyte response to β-amyloid (Aβ) has not been studied. The purpose of this study was to investigate this issue. Compared to media control, the lower concentrations of Aβ(1-42) (0.1-1 μM) increased AQP4 expression in cultured mouse cortical astrocytes, while the higher concentrations of Aβ(1-42) (10 μM) decreased AQP4 expression. AQP4 gene knockout reduced Aβ(1-42)-induced astrocyte activation and apoptosis, which was associated with a reduction in the uptake of Aβ via decreased upregulation of low-density lipoprotein receptor related protein-1. Moreover, time-course and levels of Aβ(1-42)-induced mitogen-activated protein kinase phosphorylation were altered in AQP4 null astrocytes compared with wild-type controls. Our data reveal a novel role of AQP4 in the uptake of Aβ by astrocytes, indicating that AQP4 is a molecular target for Alzheimers disease.

An ethical solution to the challenges in teaching anatomy with dissection in the Chinese culture.

Universities and medical schools in China are faced with an ongoing shortage of cadavers for education and research because of insufficient numbers of cadaver donations. This article will examine the main obstacles to cadaver donation in the Chinese culture. These include superstitious traditional views about the body, a lack of legislation regulating donations, and a deficiency of effective channels for cadaver donations. Cadaver dissection has always been the most important method of teaching anatomy to medical students. Today, ethics courses have also become essential to a complete medical education. Contemporary physicians need to be equipped to navigate the myriad of moral and ethical issues inherent to modern medicine. In China, cadaver donations lag behind those in other countries, threatening to create valid disadvantages in medical education. New legislation and public education are necessary to remove cultural barriers and change Chinese views on cadaver donation. For this reason, the Department of Human Anatomy at Nanjing Medical University has established the “Educational Center for Medical Ethics.” The goal of the Center is to promote proper respect for cadavers used for medical research and education, cherish the human lives the cadavers represent, and gain the trust of potential donors. Anat Sci Ed 1:56–59, 2008.

The distribution of neural nitric oxide synthase-positive cerebrospinal fluid-contacting neurons in the third ventricular wall of male rats and coexistence with vasopressin or oxytocin

The detailed distribution of neural nitric oxide synthase (nNOS)-positive cerebrospinal fluid-contacting neurons (CSF-CN) was studied in the wall of the third ventricle of rats by anti-nNOS immunohistochemistry. The coexistence of nNOS and 8-arginine vasopressin (AVP) or oxytocin (OT) was also investigated in the CSF-CN using double labeling immunohistochemistry. The results demonstrated a widespread occurrence of nNOS-CSF-CN throughout the wall of the hypothalamic third ventricle. The vast majority of nNOS-CSF-CN cell bodies were of magnocellular type, commonly classified as oval, fusiform, multipolar, and inverted pear shape. These cell bodies were located in the ependyma, the subependyma, or the parenchyma, and their processes inserted in the ependymal layer or directly contacted with the CSF space. Electron microscopy demonstrated many nNOS-immunoreactive somas, dendrites, and/or axons that were situated at the subependyma, the ependyma, or the supraependyma. Generally, the distribution of OT-CSF-CN in the third ventricular wall was similar to the nNOS-CSF-CN and the ratio of NOS/OT co-expression was approximately 88%. In comparison, the distribution of AVP-CSF-CN was mainly restricted to the rostral part of the third ventricle and the ratio of nNOS/AVP co-expression was only about 6%. The widespread presence of nNOS-CSF-CN-expressing OT in the third ventricular region suggests that NO is an important messenger in the CSF-hypothalamo-hypophyseal neuroendocrine regulation that may in part act in concert with OT.

Aquaporin-4 deficiency exacerbates brain oxidative damage and memory deficits induced by long-term ovarian hormone deprivation and D-galactose injection

Astrocyte dysfunction is implicated in pathogenesis of certain neurological disorders including Alzheimers disease (AD). A growing body of evidence indicates that water channel aquaporin-4 (AQP4) is a potential molecular target for the regulation astrocyte function. Recently, we reported that AQP4 expression was increased in the hippocampus of an AD mouse model established by long-term ovarian hormone deprivation combined with D-galactose (D-gal) exposure. However, pathophysiological roles and mechanisms of AQP4 up-regulation remain unclear. To address this issue, age-matched female wild-type and AQP4 null mice underwent ovariectomy, followed by D-gal administration for 8 wk. AQP4 null mice showed more severe brain oxidative stress, spatial learning and memory deficits, and basal forebrain cholinergic impairment than the wild-type controls. Notably, AQP4 null hippocampus contained more prominent amyloid-β production and loss of synapse-related proteins. These results suggested that ovariectomy and D-gal injection induced oxidative damage results in compensatory increases of AQP4 expression, and deficiency of AQP4 exacerbates brain oxidative stress and memory deficits. Therefore, regulation of astrocyte function by AQP4 may attenuate oxidative damage, offering a promising therapeutic strategy for AD.

Pathological and biochemical alterations of astrocytes in ovariectomized rats injected with d-galactose: A potential contribution to Alzheimer's disease processes

Astrocytes are implicated in the pathological changes of Alzheimers disease. Our previous studies have demonstrated that estrogen deprivation and oxidative stress act synergistically to accelerate the progress of Alzheimers disease. Long-term D-galactose injection combined with ovariectomy may serve as a rodent model for Alzheimers disease. To address the potential contribution of astroglia to the Alzheimers disease pathogenesis, we investigated pathological and biochemical alterations of astrocytes under this animal model. Ovariectomized rats injected with D-galactose for 2 weeks showed extensive localization of glial fibrillary acidic protein immunoreactive astrocytes and slightly elevated glutathione levels in the hippocampus without significant impairments in the water maze test and deficits of the cholinergic analyses, compared to the saline-injected rats. Ovariectomized rats injected with D-galactose for 6 weeks, however, exhibited degeneration of astrocytes and decreased glutathione levels in the hippocampus, accompanied with severe dysfunction of behavioral test and deficiency of cholinergic terminals. Electron microscopy further confirmed the pathological changes of astrocytes, especially in the aggregated area of synapse and brain microvessels. Consistent with degeneration of perivascular astrocytic endfeet, analysis of the horseradish peroxidase demonstrated an impairment of the blood-brain barrier permeability. These findings indicate that biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronal deficits in the course of Alzheimers disease. Restoring neuroprotective potential of astrocytes may be a useful therapeutic target for Alzheimers disease and other neurodegenerative diseases.

An overview of the roles and responsibilities of Chinese medical colleges in body donation programs.

The use of human tissue is critical for gross anatomy education in the health professions. Chinese medical colleges have faced a shortage of anatomical specimens over the past decade. While body donation plays an important role in overcoming this gap, this practice has only recently been introduced in China, and the donation rate is relatively low and fraught with a number of difficulties. In the past, traditional Chinese culture focused on preserving the human body intact, which often limited body donation. In recent years, the public has become more open toward body donation. At Nanjing Medical University, only 20 bodies were donated in 2001. After the university became involved in an organized body donation program, this number increased to 70 donated bodies per year (2007 to 2012). This article describes and reviews Chinese medical colleges as a special case study among body donation programs, particularly in terms of the multiple responsibilities and roles that such institutions must assume in the course of adopting these programs. Medical colleges in China must serve as advocates, coordinators, builders, managers, educators, and beneficiaries in undertaking body donation programs. It is important for medical colleges to recognize these pluripotent roles and educate the public in order to promote body donation programs. This case study may also effectively guide and encourage Chinese medical colleges in refining their own body donation programs in the future. Anat Sci Educ 7: 312–320.

Aerobic Exercise Combined with Antioxidative Treatment does not Counteract Moderate‐ or Mid‐Stage Alzheimer‐Like Pathophysiology of APP/PS1 Mice

The present study evaluated the combined treatment effects of aerobic exercise and antioxidative stress on moderate‐stage Alzheimers disease (AD).