Symposia
Neurovascular Inflammatory Disorder and Drug Target |
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| 1S7-1
Chronic cerebral hypoperfusion accelerates Alzheimer's disease pathology with cerebrovascular remodeling in a novel mouse model
Koji Abe，Yun Zhai，Toru Yamashita，Yumiko Nakano，Ryuta Morihara，Yasuyuki Ohta，Nozomi Hishikawa，Jingwei Shang
Dept Neurol. Okayama Univ Med Sch
Aging societies presents a strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) with vertebral white matter dysintegrity. In the present study, we created a new mouse model for AD with CCH, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. In contrast to simple APP23 mice, an additional CCH exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + CCH mice brains. CCH also exacerbated neuronal loss and decrease of α7 subunit of nicotinic acetylcholine receptors (α7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG, MMP9 expressions, and a dramatically enlarged cerebral vessels with remodeling. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment probably associated with nAChR-mediated neuroprotection by allosterically potentiating ligand (APL) action. | | 1S7-2
Receptor Tyrosine Protein Kinase ErbB4 Cleavage Is Involved in Brain Ischemia-Induced Neuronal Death
Ying-mei Lu
Sch Med, Zhejiang Univ City College
Receptor tyrosine-protein kinase ErbB4 is a member of the epidermal growth factor receptor subfamily, the precise role of ErbB4 during the pathological process of brain ischemia remains largely unknown. In the present study, we provide evidence that degradation of ErbB4 is involved in neuronal cell death in response to ischemia. Our data showed that the application of neuregulin-1β provided significant protection against oxygen-glucose deprivation (OGD)-induced neuronal death as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, annexin V/propidium iodide flow cytometry analysis and terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) staining. Furthermore, neuregulin-1β treatment significantly reduced the infarct volume of ischemic mice, and this result was not seen in the ErbB4 knockout mice. We found that brain ischemia induced the breakdown of ErbB4 in a time-dependent manner in vivo, but not that of ErbB2. In vitro studies further indicated that recombinant calpain induced the cleavage of ErbB4 in a dose-dependent way, whereas the calpain inhibitor significantly reduced the OGD-induced ErbB4 breakdown. Additionally, OGD-induced apoptosis was partially abolished by transfection with the ErbB4E872K mutant. Taken together, neuregulin-1β elicits its neuroprotective effect in an ErbB4-dependent manner, and the cleavage of ErbB4 by calpain contributes to a neuronal cell death cascade during brain ischemia. | | 1S7-3
Neural circuits basis of temporal lobe epilepsy
Zhong Chen，Yi Wang，Cenglin Xu，Zhenghao Xu，Bin Chen，Shuang Wang
Dept Pharmacol, Key Lab of Ministry of Health in China, Sch Med, Zhejiang Univ
Temporal lobe epilepsy (TLE) is a common type of epilepsy and not well controlled by current treatments, but the underlying cellular/circuit mechanisms remain unclear. The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy, which was mainly depending on the stimulation target, the stimulation frequency and stimulation time (the therapeutic-window phenomenon). Now, by using optogenetics, multiple-channel EEG analysis, imaging, electrophysiological and molecular techniques, we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation, and found that entorhinal principal neurons mediate antiepileptic “glutamatergic-GABAergic” neuronal circuit for brain stimulation treatments of epilepsy. Meanwhile, we are currently focusing on the interplay of inhibitory and excitatory network in subicular microcircuits especially that related to the generation of generalized seizures (GS) in TLE, and we found that depolarized GABAergic signaling in subicular microcircuit mediates GS in TLE. This may be of therapeutic interest in understanding the pathological neuronal circuitry and further the development of novel therapeutic approaches. | | 1S7-4
Nestin expression in neuroinflammatory conditions reveals a signal induction in neurogenesis
Yijia Lou，Luo Yunxiang，Yihai Zang，Tong Lii，Danyan Zhu，Bangxin Chen
Institute Pharmacol & Toxicol, College Pharma Sci, Zhejiang Univ
Nestin is a known marker of neuronal progenitor cells in the adult brain. In the present study, we investigate how nestin signals are controlled in the context of neuroinflammatory challenge. To visualize effects of neuroinflammation on neurogenesis, nestin induction profiles of the tissue sections were analyzed in the hippocampus in lipopolysaccharide (LPS)-induced innate immune stimuli in vivo. A context- and injury-dependent induction and cellular expression profile of nestin was displayed in SVZ and DG regions. TNF-α, IL-1β and IL-6 levels in hippocampus were enhanced after LPS injection. While in the physiological baseline conditions the nestin signal was restricted to neuronal progenitors, the expression of nestin in a high level following innate immune challenge after LPS treatment. Nerve rosette, a tubular structure, consisting of neural precursor cells appeared in the Slm region of hippocampal CA1. Meanwhile, the process of neuronal polarization appeared via cAMP-LKB1-SAD/MARK2 pathway. It suggests that neurogenesis in vivo can be influenced by extrinsic factors from the microenvironment of inflammation. The findings indicate neuronal polarization-related pathway and the possible involvement of nestin signals in disease of neuroinflammation. | | 1S7-5
Endothelial TIGAR protects tight junction integrity from excessive autophagy during hypoglycemic stress
Feng Han
Institute Pharmacol & Toxicol, College Pharma Sci, Zhejiang Univ
TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and increases flux through the pentose phosphate pathway. Here, we report that TIGAR protects brain endothelial cell tight junctions during hypoglycemia by limiting excessive autophagy. We show that the microvessel integrity was improved dramatically in TIGAR transgenic mice stressed by hypoglycemia and show further that inhibition of excessive autophagy by TIGAR preserves the integrity of tight junctions between endothelial cells. Immunoprecipitation and FRET imaging data in endothelial cells stressed by low glucose revealed that TIGAR complexes with calmodulin to promote TIGAR tyrosine nitration and inactivation. A tyrosine 92 mutation interfere with the TIGAR-dependent NADPH generation and abolish its protective effect on tight junctions. The hypoglycemia-induced disruption of tight junctions and activation of autophagy were abrogated by pharmacological blockade of nitrosative stress signaling. Collectively, these studies identify TIGAR as a new therapeutic target for reducing excessive autophagy and tight junction injury in neurovascular diseases. | | | |
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