ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion.
2017; 168 (3): 427–41.e21
Dual Regulation of miRNA Biogenesis Generates Target Specificity in Neurotrophin-Induced Protein Synthesis
2012; 148 (5): 933-946
Human apolipoprotein E (ApoE) apolipoprotein is primarily expressed in three isoforms (ApoE2, ApoE3, and ApoE4) that differ only by two residues. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), ApoE3 is neutral, and ApoE2 is protective. How ApoE isoforms influence AD pathogenesis, however, remains unclear. Using ES-cell-derived human neurons, we show that ApoE secreted by glia stimulates neuronal Aβ production with an ApoE4 > ApoE3 > ApoE2 potency rank order. We demonstrate that ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases. Activated ERK1/2 induces cFos phosphorylation, stimulating the transcription factor AP-1, which in turn enhances transcription of amyloid-β precursor protein (APP) and thereby increases amyloid-β levels. This molecular mechanism also regulates APP transcription in mice in vivo. Our data describe a novel signal transduction pathway in neurons whereby ApoE activates a non-canonical MAP kinase cascade that enhances APP transcription and amyloid-β synthesis.
View details for DOI 10.1016/j.cell.2016.12.044
View details for PubMedID 28111074
Dynamic cerebral autoregulation in carotid stenosis before and after carotid stenting
JOURNAL OF VASCULAR SURGERY
2008; 48 (1): 88-92
Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182 while selectively derepressing and increasing translation of specific mRNAs.
View details for DOI 10.1016/j.cell.2012.01.036
View details for Web of Science ID 000300985000014
View details for PubMedID 22385959
Transcranial color-coded sonography helps differentiation between idiopathic Parkinson's disease and vascular parkinsonism
JOURNAL OF NEUROLOGY
2007; 254 (4): 501-507
Impaired dynamic cerebral autoregulation (DCA) has been shown in patients with severe (> or =70%) internal carotid artery (ICA) stenosis, but DCA in moderate (50% to 69%) ICA stenosis, especially its response to carotid revascularization, has rarely been reported. Our study aimed to characterize DCA in severe and moderate ICA stenosis before and after carotid stenting.This study included 21 patients with ICA stenosis > or =50% who received carotid stenting. Data of arterial blood pressure and cerebral blood flow velocity of the middle cerebral artery, measured by transcranial Doppler, were collected for 10 minutes < or =24 hours before and after stenting. The DCA index, represented as aMx, was assessed by calculating the Pearson product-moment correlation coefficient of spontaneous arterial blood pressure and cerebral blood flow velocity fluctuations. The relationship between aMx and stenotic severity and also alternations of aMx before and after stenting were assessed.Carotid stenting was effective to improve the DCA in the stenting side but not in the contralateral nonstenting side. In considering individual ICAs, the average aMx (mean +/- SD) increased significantly from ICA stenosis <50% (0.117 +/- 0.091) to 50% to 69% (0.349 +/- 0.144), 70% to 99% (0.456 +/- 0.147), and total occlusion (0.557 +/- 0.210; P < .05, P < .01, and P < .01, compared with 50% to 69%, 70% to 99%, or total occlusion with <50% stenosis). The correlation between the degree of ICA stenosis and the aMx was also significant (r = 0.693, P < .005). The aMx improved significantly in the stented side after carotid stenting in both moderate and severe ICA stenosis, and this finding was not affected by age, sex, risk factors, or clinical symptoms.In addition to patients with severe carotid stenosis, patients with moderate carotid stenosis may also have impaired DCA that can be restored after carotid stenting.
View details for DOI 10.1016/j.jvs.2008.02.025
View details for Web of Science ID 000257227500014
View details for PubMedID 18486427
Transcranial imaging of substantia nigra hyperechogenicity in a Taiwanese cohort of Parkinson's disease
2007; 22 (4): 550-555
Recently, transcranial color-coded sonography (TCCS) has been found to have a diagnostic value in patients with idiopathic Parkinson's disease (IPD), which displays increased hyperechogenicity at the substantia nigra (SN).To use TCCS, to assess the difference in SN hyperechogenicity and intracranial hemodynamics among subjects with IPD, vascular parkinsonism (VP) and controls.Eighty IPD and 30 VP patients, and 60 controls were recruited into this study. The hyperechogenicity area at the SN and midbrain were calculated by encircling the outer circumference from the ipsilateral temporal window, using TCCS in each subject. The hemodynamics of intracranial large arteries, including flow velocity and pulsatility index (PI), were also measured.The presence of SN hyperechogenicity was significantly higher in the IPD patients than in the VP patients and controls (84% vs. 20% & 5%, respectively, p < 0.001). In IPD patients, the SN hyperechogenicity was correlated with the neurological severity and disease duration. Twenty-five (66.7%) VP patients had obvious vascular abnormality, as seen in TCCS study. The mean PI was significantly more elevated in the VP patients than those in the IPD patients and controls (all p < 0.05), but there was no significant difference of flow velocities among the VP, IPD patients and controls.TCCS, combining B-mode imaging for SN echogenicity and trancranial Doppler for intracranial hemodynamics, is a useful diagnostic tool in the differentiation between IPD and VP. These findings also suggest that multiple subcortical vascular lesions may damage the basal ganglia and thalamocortical circuit and result in parkinsonism features in VP patients.
View details for DOI 10.1007/s00415-006-0403-9
View details for Web of Science ID 000246303800015
View details for PubMedID 17401518
Transcranial Doppler imaging (TCDI) has been used as a noninvasive diagnostic tool to differentiate Parkinson's disease (PD) from atypical parkinsonism by detecting hyperechogenicity in the substantia nigra (SN). To our knowledge, no TCDI data are available for Asian populations, and TCDI sensitivity is uncertain across populations. Early-onset PD (EOPD) represents a specific PD subtype based on clinical features and pathogenic mechanisms. It is not known if EOPD patients have abnormal echogenicity in SN comparable to late-onset PD (LOPD) patients. We assessed the area of SN hyperechogenicity (hyper-SN) and a ratio of hyper-SN over ipsilateral midbrain (S/M ratio) with TCDI in 164 healthy Taiwanese, 40 EOPD patients, and 40 LOPD patients. The upper 95th percentile values for hyper-SN and S/M ratio were 0.20 cm(2) and 0.07. Our results indicate that S/M ratio is a more sensitive measure than hyper-SN in diagnosing PD. Approximately 92.5% of the LOPD patients and 57.5% of the EOPD patients had S/M ratios >/= 0.07. Enlarged hyperechogenicity of SN is a common finding in LOPD, but not in EOPD. Iron-independent mechanisms of SN cell degeneration in EOPD distinct from that in LOPD might contribute to the sonographic findings.
View details for DOI 10.1002/mds.21372
View details for Web of Science ID 000245408700019
View details for PubMedID 17260344