Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.     

Lercanidipine Rescues Hippocampus Pyramidal Neurons from Mild Ischemia-Induced Delayed Neuronal Death in SHRSP

Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipine, lisinopril, valsartan, and hydralazine on occlusion-induced DND in SHRSPs. Drugs were administered for 2 weeks, from 15 to 17 weeks of age. 0.1% Nicardipine and 0.01 or 0.03% lercanidipine were administered in the SP diet (about 61.3, 5.7, and 18.8 mg/kg/day, respectively), and the remaining drugs were administered at 10 mg/kg/day using the mini-osmotic pump. The animals were operated on at 16 weeks of age, and DND was analyzed by histological examination 1 week later. Systolic blood pressure was measured at 15, 16, and 17 weeks of age. For chronic treatment, Calcium-channel blockers were administered from 8 to 17 weeks of age. All antihypertensive drugs significantly lowered systolic blood pressure at 16 weeks of age. Hydralazine and lisinopril were associated with the greatest reduction; however, lercanidipine, nicardipine, and valsartan effectively reduced systolic blood pressure to within a medium range. DND was significantly inhibited only by 0.03% lercanidipine. Chronic treatment with 0.03% lercanidipine also protected pyramidal neurons. The results of this study demonstrate that the long-acting, lipophilic Calcium-channel blocker lercanidipine inhibits occlusion-induced DND in SHRSPs and that lercanidipine may effectively reduce dementia induced by small ischemic insults in patients with essential hypertension.     

Rice Brittle culm 6 encodes a dominant-negative form of CesA protein that perturbs cellulose synthesis in secondary cell walls

The brittle culm (bc) mutants of Gramineae plants having brittle skeletal structures are valuable materials for studying secondary cell walls. In contrast to other recessive bc mutants, rice Bc6 is a semi-dominant bc mutant with easily breakable plant bodies. In this study, the Bc6 gene was cloned by positional cloning. Bc6 encodes a cellulose synthase catalytic subunit, OsCesA9, and has a missense mutation in its highly conserved region. In culms of the Bc6 mutant, the proportion of cellulose was reduced by 38%, while that of hemicellulose was increased by 34%. Introduction of the semi-dominant Bc6 mutant gene into wild-type rice significantly reduced the percentage of cellulose, causing brittle phenotypes. Transmission electron microscopy analysis revealed that Bc6 mutation reduced the cell wall thickness of sclerenchymal cells in culms. In rice expressing a reporter construct, BC6 promoter activity was detected in the culms, nodes, and flowers, and was localized primarily in xylem tissues. This expression pattern was highly similar to that of BC1, which encodes a COBRA-like protein involved in cellulose synthesis in secondary cell walls in rice. These results indicate that BC6 is a secondary cell wall-specific CesA that plays an important role in proper deposition of cellulose in the secondary cell walls.     

Phosphatidylglucoside: a novel marker for adult neural stem cells

We investigated the expression of a novel glycophospholipid, phosphatidylglucoside (PtdGlc), in adult mouse brains. Immunohistochemical analysis with DIM21 antibody, a monoclonal anti-PtdGlc antibody, revealed robust PtdGlc staining in the two primary neurogenic regions of the adult rodent brain, the subventricular zone (SVZ) lining the lateral ventricle and the subgranular zone of the dentate gyrus. Intriguingly, the staining pattern of PtdGlc appeared to overlap that of glial fibrillary acidic protein, an adult neural stem cell marker in these regions. Further immunohistochemical analysis revealed that PtdGlc expression on the cell membranes of adult SVZ neural stem cells significantly overlapped with other proposed adult neural stem cell markers. Moreover, PtdGlc(+) cells isolated from adult mouse SVZs by fluorescence-activated cell sorting with anti-PtdGlc antibody efficiently generated neurospheres in cell culture. These cells differentiated into neurons, astrocytes, and oligodendrocytes in vitro, directly demonstrating that PtdGlc-expressing cells possessed multipotency. Our data suggest that PtdGlc could be a useful adult stem cell marker.     

The presence of mercury selenide in various tissues of the striped dolphin: evidence from μ-XRF-XRD and XAFS analyses

Marine mammals accumulate mercury in their tissues at high concentration and detoxify by forming mercury selenide (HgSe, tiemannite) mainly in the liver. We investigated the possibility of formation of HgSe in various tissues (liver, kidney, lung, spleen, pancreas, muscle and brain) other than the liver of the striped dolphin (Stenella coeruleoalba). We applied a combination method of micro-X-ray fluorescence (μ-XRF) imaging and micro-X-ray diffraction (μ-XRD) using a synchrotron radiation X-ray microbeam to analyze the tissue samples directly with minimal sample preparation. By this method, many accumulation points for Hg and Se on a micron scale were found in thin sections of the spleen and liver tissue and consequently, the XRF spectra and the XRD pattern of the hot spots confirmed the presence of tiemannite, HgSe. On the other hand, the insoluble fractions after enzyme digestion of the nuclear and mitochondrial fractions of all tissues were subjected to X-ray absorption fine structure (XAFS) analysis. XAFS analysis confirmed the presence of HgSe in all the tissues examined (liver, kidney, lung, spleen, pancreas, muscle and brain) of the striped dolphin. The presence of HgSe in all the tissues examined suggests that Se would be involved in the detoxification process of Hg in various tissues other than the liver. This contribution seems to be large especially in the liver and spleen but relatively small in the kidney, pancreas and brain, because the proportion of insoluble fraction containing HgSe was lower in these tissues (25 to 46%). This is the first report on the presence of tiemannite HgSe in various tissues of marine mammals.     

Proteomics portrait of archival lesions of chronic pancreatitis

Chronic pancreatitis is a chronic inflammatory disorder of the pancreas. The etiology is multi-fold, but all lead to progressive scarring and loss of pancreatic function. Early diagnosis is difficult; and the understanding of the molecular events that underlie this progressive disease is limited. In this study, we investigated differential proteins associated with mild and severe chronic pancreatitis in comparison with normal pancreas and pancreatic cancer. Paraffin-embedded formalin-fixed tissues from five well-characterized specimens each of normal pancreas (NL), mild chronic pancreatitis (MCP), severe chronic pancreatitis (SCP) and pancreatic ductal adenocarcinoma (PDAC) were subjected to proteomic analysis using a "label-free" comparative approach. Our results show that the numbers of differential proteins increase substantially with the disease severity, from mild to severe chronic pancreatitis, while the number of dysregulated proteins is highest in pancreatic adenocarcinoma. Important functional groups and biological processes associated with chronic pancreatitis and cancer include acinar cell secretory proteins, pancreatic fibrosis/stellate cell activation, glycoproteins, and inflammatory proteins. Three differential proteins were selected for verification by immunohistochemistry, including collagen 14A1, lumican and versican. Further canonical pathway analysis revealed that acute phase response signal, prothrombin activation pathway, and pancreatic fibrosis/pancreatic stellate cell activation pathway were the most significant pathways involved in chronic pancreatitis, while pathways relating to metabolism were the most significant pathways in pancreatic adenocarcinoma. Our study reveals a group of differentially expressed proteins and the related pathways that may shed light on the pathogenesis of chronic pancreatitis and the common molecular events associated with chronic pancreatitis and pancreatic adenocarcinoma.