BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Na(v)1) beta2-subunit (beta2), a type I membrane protein that covalently binds to Na(v)1 alpha-subunits, is a substrate for BACE1 and gamma-secretase. Here, we find that BACE1-gamma-secretase cleavages release the intracellular domain of beta2, which increases mRNA and protein levels of the pore-forming Na(v)1.1 alpha-subunit in neuroblastoma cells. Similarly, endogenous beta2 processing and Na(v)1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Na(v)1.1 is retained inside the cells and cell surface expression of the Na(v)1 alpha-subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice. BACE1, by cleaving beta2, thus regulates Na(v)1 alpha-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity.

Recent genome-wide association studies indicate that a simple alteration of Leucine-rich repeat kinase 2 (LRRK2) gene expression may contribute to the etiology of sporadic Parkinson's disease (PD). However, the expression and regulation of LRRK2 protein in the sporadic PD brains remain to be determined. Here, we found that the expression of LRRK2 protein was enhanced in the sporadic PD patients using the frontal cortex tissue from a set of 16 PD patients and 7 control samples. In contrast, no significant difference was detected in the level of LRRK2 mRNA expression between the control and PD cases, suggesting a potential post-transcriptional modification of the LRRK2 protein expression in the sporadic PD brains. Indeed, it was identified that microRNA-205 (miR-205) suppressed the expression of LRRK2 protein through a conserved-binding site at the 3'-untranslated region (UTR) of LRRK2 gene. Interestingly, miR-205 expression was significantly downregulated in the brains of patients with sporadic PD, showing the enhanced LRRK2 protein levels. Also, in vitro studies in the cell lines and primary neuron cultures further established the role of miR-205 in modulating the expression of LRRK2 protein. In addition, introduction of miR-205 prevented the neurite outgrowth defects in the neurons expressing a PD-related LRRK2 R1441G mutant. Together, these findings suggest that downregulation of miR-205 may contribute to the potential pathogenic elevation of LRRK2 protein in the brains of patients with sporadic PD, while overexpression of miR-205 may provide an applicable therapeutic strategy to suppress the abnormal upregulation of LRRK2 protein in PD.

Context: Elevated ␤-secretase (␤-site amyloid precursor protein-cleaving enzyme 1 [BACE1]) activity has been found in the brains of patients with sporadic Alzheimer disease (AD) compared with controls. Now we are particularly interested in whether BACE1 can be identified in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI), a population at high risk for AD. The possible presence of BACE1 in the CSF of patients with AD and MCI has so far gone unreported.Objective: To examine whether BACE1 can be identified in the CSF of patients with MCI.Design: We evaluated CSF BACE1 levels using 2 sandwich enzyme-linked immunosorbent assays, BACE1 enzymatic activities by means of synthetic fluorescence substrate, and total amyloid-␤ peptide levels using a sandwich enzyme-linked immunosorbent assay.Setting: Two independent research centers.Participants: Eighty patients with sporadic AD, 59 patients with MCI, and 69 controls.Main Outcome Measures: BACE1 levels and enzymatic activities and amyloid-␤ peptide levels. Conclusion: Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD. Psychiatry. 2007;64:718-726 A LZHEIMER DISEASE (AD) IS characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the 4-kDa amyloid-␤ peptide (A␤) in the brain. Arch Gen1 ␤-Secretase (␤-site amyloid precursor protein-cleaving en-2 is one of the 2 key enzymes in amyloid precursor protein (APP) processing. Amyloid-␤ peptide results from cleavage of APP initially by BACE1 to produce a C99 fragment and release soluble APP␤; C99 is then further cleaved by ␥-secretase, leading to A␤. Increased BACE1 activity and elevated levels of insoluble A␤ have been shown in the brains of patients with sporadic AD. 3,4 Because cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the central nervous system, biochemical changes in the brain could potentially be reflected in CSF. The CSF-based detection of BACE1 levels and activity might be valuable in aiding the early diagnosis of AD, especially in patients with mild cognitive impairment (MCI), who show a higher risk of AD.5 Several recent studies [6][7][8] showed that BACE1 activity can be detected in the CSF. However, whether changes could occur in BACE1 activity or protein levels in the CSF of patients with AD or MCI remains unknown.In the present study, we quantitatively analyzed the enzymatic activities and protein levels of BACE1 and total A␤ levels in CSF samples from 208 individuals. We aim to determine whether BACE1 levels and activity can be detected in CSF, whether they are altered in AD compared with healthy aging, and whether levels of BACE1 protein and activity may be useful to discriminate patients with AD or MCI from healthy individuals.

Long non-coding RNA (lncRNA) activated by TGF-β (ATB) has been reported to be widely expressed in different types of cancer; however, the function of ATB in lung cancer remains unclear. In order to elucidate the role of ATB in lung cancer, reverse transcription-quantitative polymerase chain reaction was used to detect the expression of ATB in tumor tissues and corresponding non-tumor lung tissues from 32 patients with lung cancer. Furthermore, the association between the expression of ATB and clinical characteristics was investigated. Cell proliferation was assessed using a cell counting kit-8 assay and cell migration was assessed using a wound healing assays. Epithelial-mesenchymal-transition and mitogen-activated protein kinase signaling pathway activity was examined using western blotting. It was demonstrated that ATB was highly expressed in lung cancer tissues compared with noncancerous tissues, and associated with tumor size and metastasis. It was also demonstrated that ATB was highly expressed in the lung cancer cell lines, A549 and HCC827, compared with the HBE-1 cell line. Suppression of ATB significantly inhibited the proliferation and migratory rate of lung cancer cells. The protein expression levels of p38, E-cadherin and N-cadherin were altered by suppression of ATB expression. Overall, the present study demonstrated that ATB may promote the development of lung cancer.

Aggf1 is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the in vivo roles of Aggf1 are incompletely defined. Here we demonstrate that Aggf1 is essential for both physiological angiogenesis and pathological tumour angiogenesis in vivo. Two lines of Aggf1 knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for Vegfa and Dll4. Aggf1+/- KO caused defective angiogenesis in yolk sacs and embryos. Survived adult heterozygous mice exhibit frequent haemorrhages and increased vascular permeability due to increased phosphorylation and reduced membrane localization of VE-cadherin. AGGF1 inhibits VE-cadherin phosphorylation, increases plasma membrane VE-cadherin in ECs and in mice, blocks vascular permeability induced by ischaemia-reperfusion (IR), restores depressed cardiac function and contraction, reduces infarct sizes, cardiac fibrosis and necrosis, haemorrhages, edema, and macrophage density associated with IR. Mechanistically, AGGF1 promotes angiogenesis by activating catalytic p110α subunit and p85α regulatory subunit of PI3K, leading to activation of AKT, GSK3β and p70S6K. AKT activation is significantly reduced in heterozygous KO mice and isolated KO ECs, which can be rescued by exogenous AGGF1. ECs from KO mice show reduced capillary angiogenesis, which is rescued by AGGF1 and AKT. Tumour growth/angiogenesis is reduced in heterozygous mice, which was associated with reduced activation of p110α, p85α and AKT. Together with recent identification of somatic mutations in p110α (encoded by PIK3CA), our data establish a potential mechanistic link between AGGF1 and PIK3CA, the two genes identified for KTS.