Donghua Zou

The role of microglia in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Microglia are the resident innate immune cells in the CNS; they play an important role in the processes of demyelination and remyelination in MS. Microglia can function as antigen-presenting cells and phagocytes. In the past, microglia were considered to be the same cell type as macrophages, and researchers have different opinions about the role of microglia in MS. This review focuses on the original classification of microglia and their role in the pathogenesis of MS. Moreover, we present a hypothetical model for the role of microglia in the pathogenesis of MS based on recent findings.

Grouping Pentylenetetrazol-Induced Epileptic Rats According to Memory Impairment and MicroRNA Expression Profiles in the Hippocampus

Previous studies have demonstrated a close relationship between abnormal regulation of microRNA (miRNA) and various types of diseases, including epilepsy and other neurological disorders of memory. However, the role of miRNA in the memory impairment observed in epilepsy remains unknown. In this study, a model of temporal lobe epilepsy (TLE) was induced via pentylenetetrazol (PTZ) kindling in Sprague-Dawley rats. First, the TLE rats were subjected to Morris water maze to identify those with memory impairment (TLE-MI) compared with TLE control rats (TLE-C), which presented normal memory. Both groups were analyzed to detect dysregulated miRNAs in the hippocampus; four up-regulated miRNAs (miR-34c, miR-374, miR-181a, and miR-let-7c-1) and seven down-regulated miRNAs (miR-1188, miR-770-5p, miR-127-5p, miR-375, miR-331, miR-873-5p, and miR-328a) were found. Some of the dysregulated miRNAs (miR-34c, miR-1188a, miR-328a, and miR-331) were confirmed using qRT-PCR, and their blood expression patterns were identical to those of their counterparts in the rat hippocampus. The targets of these dysregulated miRNAs and other potentially enriched biological signaling pathways were analyzed using bioinformatics. Following these results, the MAPK, apoptosis and hippocampal signaling pathways might be involved in the molecular mechanisms underlying the memory disorders of TLE.

Cognitive deficits are ameliorated by reduction in amyloid β accumulation in Tg2576/p75NTR +/− mice

AIMS Amyloid β (Aβ) is considered to be an important mediator of the development and progression of Alzheimers disease (AD). Its direct binding to p75(NTR), not TrkA, induces apoptosis, which is thought to be the most relevant feature of p75(NTR) regarding AD. In the present study we explored the regulation of p75(NTR) on Aβ production and accumulation during AD pathology. MATERIALS AND METHODS We generated Tg2576/p75(NTR+/-) mice by crossing the transgenic AD mice (Tg2576) with p75(NTR-/-) mice to lower the p75(NTR) level. Under these conditions, we evaluated cognitive function using the Morris water maze, pathology and process by which two types of Aβ (Aβ40 and Aβ42) are produced, by enzyme-linked immunosorbent assay and Western blotting. KEY FINDING The results showed that cognitive deficits were rescued in Tg2576/p75(NTR+/-) mice compared with those in Tg2576 mice. This cognitive functional recovery may be a consequence of a reduction in Aβ accumulation through the inhibition of β- and γ-secretase activities, without altering α-secretase activity. SIGNIFICANCE Here, we investigated the mechanism by which p75(NTR) regulates Aβ production and accumulation. Better understanding the relationship between p75(NTR) and Aβ producing may help taking insight into the AD pathology.

miR-34a knockout attenuates cognitive deficits in APP/PS1 mice through inhibition of the amyloidogenic processing of APP

&NA; The noncoding miRNA‐34a (miR‐34a) is involved in Alzheimers disease (AD) pathologenesis and shows potential for application as a biomarker for early diagnosis and intervention. Here, we established miR‐34a knockout mice in an APP/PS1 background (APP/PS1‐miR‐34a KO mice) by crossbreeding miR‐34a−/− mice with APP/PS1 mice. We then investigated cognitive impairment and related pathologies. The results showed that the level of miR‐34a was increased at about 6 months in APP/PS1 mice, consistent with the increase in amyloid &bgr; (A&bgr;), and cognitive function was significantly improved in mice when miR‐34a was knocked out in 9‐month‐old and 12‐month‐old mice, indicating that miR‐34a is a potential candidate for determining the progression of AD. Furthermore, we assessed the processing of amyloid precursor protein (APP) and the results suggest that cognitive improvement by miR‐34a knock out was mainly triggered by depression of &ggr;‐secretase activity, without affecting &bgr;‐ and &agr;‐secretase activities, indicating that miR‐34a plays an important role in AD pathology, mainly by inhibiting the amyloidogenic processing of APP, without altering the non‐amyloidogenic processing of APP.

The genetic relationship between epilepsy and hemiplegic migraine

Epilepsy and migraine are common diseases of the nervous system and share genetic and pathophysiological mechanisms. Familial hemiplegic migraine is an autosomal dominant disease. It is often used as a model of migraine. Four genes often contain one or more mutations in both epilepsy and hemiplegic migraine patients (ie, CACNA1A, ATP1A2, SCN1A, and PRRT2). A better understanding of the shared genetics of epilepsy and hemiplegic migraine may reveal new strategic directions for research and treatment of both the disorders.

Role of miR-34c in the cognitive function of epileptic rats induced by pentylenetetrazol

Studies suggest that microRNA (miR)-34c may serve a role in cognitive function in rodent and primate groups. A previous study demonstrated an increase in miR-34c expression in chronic epileptic rats with memory disorders, induced by pentylenetetrazol (PTZ). However, the mechanism underlying the effects of miR-34c on cognitive function in epileptic rats remains unclear. Therefore, the present study investigated alterations in cognitive function in temporal lobe epileptic rats, induced by repeated injections of PTZ, following treatment with an miR-34c agomir compared with a scramble group. Increased expression of miR-34c was observed in the agomir group, in addition to an increased deficit in learning and memory function in the Morris water maze test. Glutamate receptor ionotropic N-methyl-D-aspartate (NMDA) 2B (NR2B), phosphorylated (p)-reduced nicotinamide-adenine dinucleotide phosphate-dependent diflavin oxidoreductase 1 (NR1) and p-glutamate receptor 1 (GluR1) protein expression was detected in the hippocampus using western blotting. Additionally, the downregulation of NR2B, p-NR1 and p-GluR1 in the miR-34c agomir group demonstrated that miR-34c may serve a negative role in cognitive function in epileptic seizures, by dysregulating NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, which are associated with long-term potentiation.

MicroRNA expression profiles in chronic epilepsy rats and neuroprotection from seizures by targeting miR-344a

MicroRNA (miRNA) is believed to play a crucial role in the cause and treatment of epilepsy by controlling gene expression. However, it is still unclear how miRNA profiles change after multiple prolonged seizures and aggravation of brain injury in chronic epilepsy (CE). To investigate the role of miRNA in epilepsy, we utilized the CE rat models with pentylenetetrazol (PTZ) and miRNA profiles in the hippocampus. miRNA profiles were characterized using miRNA microarray analysis and were compared with the rats in the sham group, which received 0.9% physiological saline treatment at the same dose. Four up-regulated miRNAs (miR-139–3p, -770–5p, -127–5p, -331–3p) and 5 down-regulated miRNAs (miR-802–5p, -380–5p, -183–5p, -547–5p, -344a/-344a–5p) were found in the CE rats (fold change >1.5, P<0.05). Three of the dysregulated miRNAs were validated by quantitative real-time polymerase chain reaction, which revealed an outcome consistent with the initial results of the miRNA microarray analyses. Then, miR-344a agomir was intracerebroventricularly injected and followed by PTZ induction of CE models to investigate the effect of miR-344a in chronic neocortical epileptogenesis. After miRNA-344a agomir and scramble treatment, results showed a restoration of seizure behavior and a reduction in neuron damage in the cortex in miRNA-334a agomir treated rats. These data suggest that miRNA-344a might have a small modulatory effect on seizure-induced apoptosis signaling pathways in the cortex.

MicroRNA-328a regulates water maze performance in PTZ-kindled rats

The down-regulation of microRNA-328a (miR-328a) in pentylenetetrazole (PTZ)-kindled rats with memory impairment was demonstrated in our previous study, while any contribution of miR-328a to cognitive dysfunction of PTZ-kindled rats remains unknown. In this study we have investigated the effect and the underlying mechanism of miR-328a on the cognitive function in PTZ-kindled rats. 48 SD male rats were divided into 4 groups as follows: a PTZ kindled group, a miR-328a antagomir group, an antagomir-control group, and a sham group (n=12 for each). All rats except those from the sham group were treated with PTZ 14 times at intervals of 48h to establish the temporal lobe epilepsy (TLE) models, and miR-328a antagomir was given to the antagomir group as a treatment by lateral-ventricle injection the day after the first injection of PTZ. Morris water maze (MWM) test was performed to assay their learning and memory abilities. The down-regulation of miR-328a in the PTZ group was confirmed using RT-qPCR and the expression of miR-328a was diminished after antagomir treatment (P<0.05). In the probe test of water maze, the time and distance of the PTZ group were both shorter than those of the sham group (P<0.05), and those of the antagomir-control group were both longer than those of the antagomir group (P<0.05). In addition, we found that with the down-regulation of miR-328a, the levels of Beta-site APP-cleaving enzyme (BACE), which is a bioinformatics-predicted target of miR-328a, were up-regulated. These findings suggest that miR-328a may play a role in memory dysfunction in PTZ-kindled rats by regulating the BACE levels and this links the PTZ model with Alzheimers disease.