Familial Danish dementia young Knock-in rats expressing humanized APP and human Aβ show impaired pre and postsynaptic glutamatergic transmission

Familial British and Danish dementia (FBD and FDD) are two neurodegenerative disorders caused by mutations in the Integral membrane protein 2B (ITM2b). BRI2, the protein encoded by ITM2b, tunes excitatory synaptic transmission at both pre- and post-synaptic terminus. Too, BRI2 interacts with and modulates proteolytic processing of Amyloid-β precursor Protein (APP), whose mutations cause familial forms of Alzheimer disease (FAD). To study pathogenic mechanism triggered by the Danish mutation we generated rats carrying the Danish mutation into the rat Itm2b gene (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human Aβ, a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles, to produce human Aβ. Here, we studied young Itm2bD rats to investigate early pathogenic changes. We found that peri-adolescent Itm2bD rats present subtle changes in human Aβ levels along with decreased spontaneous glutamate release and AMPAR-mediated responses, but increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These changes are similar to those observed in adult mice producing rodent Aβ and carrying either the Danish or British mutations into the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses; these functional alterations are detected across species and occur early in life. Future studies will be needed to determine whether this phenomenon represents an early pathogenic event in human dementia.

Leptomeningeal collateral activation indicates severely impaired cerebrovascular reserve capacity in patients with symptomatic unilateral carotid artery occlusion

For patients with symptomatic unilateral internal carotid artery (ICA) occlusion, impaired cerebrovascular reactivity (CVR) indicates increased stroke risk. Here, the role of collateral activation remains a matter of debate, whereas angio-anatomical collateral abundancy does not necessarily imply sufficient compensatory flow provided. We aimed to further elucidate the role of collateral activation in the presence of impaired CVR. From a prospective database, 62 patients with symptomatic unilateral ICA occlusion underwent blood oxygenation-level dependent (BOLD) fMRI CVR imaging and a transcranial Doppler (TCD) investigation for primary and secondary collateral activation. Descriptive statistic and multivariate analysis were used to evaluate the relationship between BOLD-CVR values and collateral activation. Patients with activated secondary collaterals exhibited more impaired BOLD-CVR values of the ipsilateral hemisphere (p = 0.02). Specifically, activation of leptomeningeal collaterals showed severely impaired ipsilateral hemisphere BOLD-CVR values when compared to activation of ophthalmic collaterals (0.05 ± 0.09 vs. 0.12 ± 0.04, p = 0.005). Moreover, the prediction analysis showed leptomeningeal collateral activation as a strong independent predictor for ipsilateral hemispheric BOLD-CVR. In our study, ipsilateral leptomeningeal collateral activation is the sole collateral pathway associated with severely impaired BOLD-CVR in patients with symptomatic unilateral ICA occlusion.

Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma

Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer.

Deficiency of the RIβ subunit of protein kinase A causes body tremor and impaired fear conditioning memory in rats

The RIβ subunit of cAMP-dependent protein kinase (PKA), encoded by Prkar1b, is a neuronal isoform of the type I regulatory subunit of PKA. Mice lacking the RIβ subunit exhibit normal long-term potentiation (LTP) in the Schaffer collateral pathway of the hippocampus and normal behavior in the open-field and fear conditioning tests. Here, we combined genetic, electrophysiological, and behavioral approaches to demonstrate that the RIβ subunit was involved in body tremor, LTP in the Schaffer collateral pathway, and fear conditioning memory in rats. Genetic analysis of WTC-furue, a mutant strain with spontaneous tremors, revealed a deletion in the Prkar1b gene of the WTC-furue genome. Prkar1b-deficient rats created by the CRISPR/Cas9 system exhibited body tremor. Hippocampal slices from mutant rats showed deficient LTP in the Schaffer collateral–CA1 synapse. Mutant rats also exhibited decreased freezing time following contextual and cued fear conditioning, as well as increased exploratory behavior in the open field. These findings indicate the roles of the RIβ subunit in tremor pathogenesis and contextual and cued fear memory, and suggest that the hippocampal and amygdala roles of this subunit differ between mice and rats and that rats are therefore beneficial for exploring RIβ function.

Pelvic collateral pathway during endovascular aortoiliac aneurysm repair with internal iliac artery interruption: a retrospective observational study

Background Ipsilateral branches of the deep femoral artery (DFA) are qualitatively identified as collateral arteries based on angiography after internal iliac artery (IIA) interruption. The purpose of this study was to quantitatively identify the major collateral pathway after unilateral IIA interruption during endovascular aortoiliac aneurysm repair to preserve the pelvic circulation and reduce the risk of ischemic complications. Methods The study population included 28 patients (mean age 76.3 years) with aortoiliac aneurysm who underwent endovascular aneurysm repair with unilateral IIA interruption from August 2012 to January 2020. The diameters of the bilateral preoperative and postoperative DFA, lateral femoral circumflex artery (LFCA), medial femoral circumflex artery (MFCA) and obturator artery (ObA) were measured on contrast-enhanced computed tomography using a 3-dimensional image analysis system. The measured values were evaluated and analyzed with a repeated measures two-way analysis of variance and Dunnett’s test. Results The postoperative diameters of the MFCA (P = 0.051) and ObA (P = 0.016) were observed to be larger than the preoperative diameters. Such increases in the MFCA (P < 0.001) and ObA (P < 0.001) diameters were only found to be significant on the unilateral side of the IIA interruption, and the diameter of the ipsilateral LFCA (P < 0.001) was also found to have significantly increased in size. However, no significant arterial extension was found on the contralateral side. Conclusions The ipsilateral MFCA-ObA pathway might therefore be a major collateral pathway arising from the DFA to preserve pelvic circulation after unilateral IIA interruption.

A Rare Intracerebral Collateral Circulation Pathway from the Contralateral Vertebral Artery to the Ipsilateral Posterior Inferior Cerebellar Artery-V4 Segment Steal

Background: Interrupted blood flow during ischemia can be compensated through collateral circulation when a cerebral artery is severely stenotic or occluded. We suppose that potential collateral pathway may exist in patients with vertebral artery occlusive disease (VAOD) around V4 segment due to the ipsilateral posterior inferior cerebellar artery (PICA) is sometimes patented after VAOD in the V4 segment.Methods: We retrospectively examined the medical database of 60 patients with VAOD admitted to the Department of Neurology from the Sixth medical center of the Chinese People's Liberation Army General Hospital and the Second Affiliated Hospital of Qiqihar Medical University from June 2018 to November 2019. The pathways which supplied PICA were investigated by digital subtraction angiography (DSA).Results: 18 patients were proximal to the exit point of the PICA among all 60 patients with VAOD in V4 segment cases, and 7 individuals (11.7%) had the collateral circulation pathway via the contralateral vertebral artery (VA) ® vertebrobasilar junction ® ipsilateral VA ® ipsilateral PICA in the DSA.Conclusions: There is an underestimated intracerebral collateral circulation pathway when VAOD from the contralateral VA to the Ipsilateral PICA, we name this phenomenon "V4 segment steal."

Novel Morphological Alteration and Neural Pathway of NADPH Diaphorase Positivity in the Spinal Cord with Disc Herniation of Aged Dog: A Case Report

Neuronal lesion or injury is a traditional approach to investigate neural circuit. Is any new neural pathway or new neurodegeneration related central nerve system injury? Spinal disc herniation can cause the spinal cord injury. However, the histological examination is still lack. It happened that a case of spinal disc herniation of a 10-year old dog was examined with NADPH diaphorase (N-d) histology. We did not find the N-d neurodegenerative aberrant in the tissue of the mid-rostral lumber segment besides the metamorphoses by the compression of the disc herniation. However, the severe neuropathological changes majorly occurred in the lumbosacral spinal cord. We found more diverse neurodegenerative alterations: the aging-related N-d body (ANB), megaloneurite and N-d homogeneous formazan globule in the lumbosacral spinal cord. We also found that a new circuit pathway (intermedial collateral pathway) showed by a megaloneurite between the lateral collateral pathway and the medial collateral pathway. The enormous notch caused by spinal disc herniation located at the mid-rostral lumber segments. The aging-related neurodegeneration occurred the specific lumbosacral segments. The homogeneous formazan globule was round or oval homogeneous N-d positivity which distributed in the gray matter and dorsal column. In the medulla oblongata, ANBs were revealed in the gracile nucleus, nucleus reticularis lateralis (ventrolateral spinal trigeminal nucleus) and middle of the spinal trigeminal nucleus.

Neuroprotective and long term potentiation improving effects of vitamin E in juvenile hypothyroid rats

Protective effects of vitamin E (Vit E) on long term potentiation (LTP) impairment, neuronal apoptosis and increase of nitric oxide (NO) metabolites in the hippocampus of juvenile rats were examined. The rats were grouped (n=13) as: (1) control; (2) hypothyroid (Hypo) and (3) Hypo-Vit E. Propylthiouracil (PTU) was given in drinking water (0.05%) during 6 weeks. Vit E (20 mg/ kg) was daily injected (IP). To evaluate synaptic plasticity, LTP from the CA1 area of the hippocampus followed by high frequency stimulation to the ipsilateral Schafer collateral pathway was carried out. The cortical and hippocampal tissues were then removed to measure NO metabolites. The brains of 5 animals in each group were removed for apoptosis study. The hypothyroidism status decreased the slope, 10–90% slope and amplitude of field excitatory post synaptic potential (fEPSP) compared to the control group (P<0.01–P<0.001). Injection of Vit E increased the slope, 10–90% slope and amplitude of the fEPSP in the Hypo-Vit E group in comparison to the Hypo group (P<0.05–P<0.01). TUNEL positive neurons and NO metabolites were higher in the hippocampus of the Hypo rats, as compared to those in the hippocampus of the control ones (P<0.001). Treatment of the Hypo rats by Vit E decreased apoptotic neurons (P<0.01–P<0.001) and NO metabolites (P<0.001) in the hippocampus compared to the Hypo rats. The results of the present study showed that Vit E prevented the LTP impairment and neuronal apoptosis in the hippocampus of juvenile hypothyroid rats.