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We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-[beta] peptides (A[beta]) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade A[beta], we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe[sup.-/-] astrocytes do not degrade A[beta] present in A[beta] plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or A[beta], or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks A[beta] degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe[sup.-/-] astrocytes do not respond to or internalize A[beta] deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited A[beta] species by astrocytes, a process that may be impaired in Alzheimer disease., Author(s): Milla Koistinaho [1, 4]; Suizhen Lin [1, 4]; Xin Wu [1]; Michail Esterman [2]; Deanna Koger [1]; Jeffrey Hanson [2]; Richard Higgs [3]; Feng Liu [1]; Seema Malkani [1]; [...]

We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-ß peptides (Aß) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Aß, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe-/- astrocytes do not degrade Aß present in Aß plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Aß, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Aß degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe-/- astrocytes do not respond to or internalize Aß deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Aß species by astrocytes, a process that may be impaired in Alzheimer disease. [ABSTRACT FROM AUTHOR]

High intraocular pressure (IOP)-induced retinal ischemia leads to acute glaucoma, which is one of the leading causes of irreversible visual-field loss, characterized by loss of retinal ganglion cells (RGCs) and axonal injury in optic nerves (ONs). Oxidative stress and the inflammatory response play an important role in the ischemic injury of retinal and optic nerves. We focus on 5α-androst-3β, 5α, 6β-triol (TRIOL), a synthetic neuroactive derivative of natural marine steroids 24-methylene-cholest-3β, 5α, 6β, 19-tetrol and cholestane-3β, 5α, 6β-triol, which are two neuroactive polyhydroxysterols isolated from the soft coral Nephthea brassica and the gorgonian Menella kanisa, respectively. We previously demonstrated that TRIOL was a neuroprotective steroid with anti-inflammatory and antioxidative activities. However, the potential role of TRIOL on acute glaucoma and its underlying mechanisms remains unclear. Here, we report TRIOL as a promising neuroprotectant that can protect RGCs and their axons/dendrites from ischemic-reperfusion (I/R) injury in an acute intraocular hypertension (AIH) model. Intravitreal injection of TRIOL significantly alleviated the loss of RGCs and the damage of axons and dendrites in rats and mice with acute glaucoma. As NF-E2-related factor 2 (Nrf2) is one of the most critical regulators in oxidative and inflammatory injury, we further evaluated the effect of TRIOL on Nrf2 knockout mice, and the neuroprotective role of TRIOL on retinal ischemia was not observed in Nrf2 knockout mice, indicating that activation of Nrf2 is responsible for the neuroprotection of TRIOL. Further experiments demonstrated that TRIOL can activate and upregulate Nrf2, along with its downstream hemeoxygenase-1 (HO-1), by negative regulation of Kelch-like ECH (Enoyl-CoA Hydratase) associated Protein-1 (Keap1). In conclusion, our study shed new light on the neuroprotective therapy of retinal ischemia and proposed a promising marine drug candidate, TRIOL, for the therapeutics of acute glaucoma.

Background: Malignant glioma is the most common brain cancer with devastating prognosis. Recurrence of malignant glioma following surgery is very common with few preventive and therapeutic options. Novel targets and therapeutic agents are constantly sought for better outcome. Our previous study established that inhibition of transient receptor potential melastatin 7 (TRPM7) channels resulted in significant decrease of human glioma cell growth and proliferation. As local anesthetic lidocaine has been shown to inhibit TRPM7 currents, we hypothesize that lidocaine may suppress glioma cell proliferation through TRPM7 channel inhibition., Methods: TRPM7 currents were recorded in rat C6 glioma cells using the whole cell patch clamp technique. Cell growth and proliferation were assessed under microscopic examination and biochemical assays., Results: Lidocaine inhibits TRPM7-like currents in a dose-dependent and reversible manner. At 1 and 3 mM, it inhibits ~30% and ~50% of TRPM7 currents. At these concentrations, it is effective in inhibiting the proliferation of C6 cells. As expected, the TRPM7 inhibitors gadolinium and 2-Aminoethoxydiphenyl borate have similar effects on TRPM7 currents and proliferation of C6 cells. Similar to its effect on C6 cells, lidocaine inhibits the proliferation of A172 cells, a human glioblastoma cell line., Conclusions: Lidocaine significantly inhibits the proliferation of glioma cells. The effect of lidocaine is mediated, at least in part, by inhibiting TRPM7 channels., Competing Interests: None.

More and more cancer patients receive surgery and chronic pain control. Cell-mediated immunosuppression from surgical stress renders perioperative period a vulnerable period for tumor metastasis. Retrospective studies suggest that regional anesthesia reduces the risk of tumor metastasis and recurrence. This benefit may be due to the attenuation of immunosuppression by regional anesthesia. On the other hand, accumulating evidence points to a direct role of anesthetics in tumor progression. A variety of malignancies exhibit increased activity of voltage-gated sodium channels. Blockade of these channels by local anesthetics may help inhibit tumor progression. Opioids promote angiogenesis, cancer cell proliferation and metastasis. It will be interesting to examine the therapeutic potential of peripheral opioid antagonists against malignancy. Volatile anesthetics are organ-protective against hypoxia, however; this very protective mechanism may lead to tumor growth and poor prognosis. In this review, we examine the direct effects of anesthetics in tumor progression in hope that a thorough understanding will help to select the optimal anesthetic regimens for better outcomes in cancer patients.

To investigate the role of human apolipoprotein E (apoE) on Abeta deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and Abeta peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain Abeta and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain Abeta deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of Abeta42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain Abeta burden, and the majority of apoE was associated with Abeta. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 < E3 << E2), resulting in early and dramatic apoE isoform-dependent effects on brain Abeta levels (E4 >> E3 > E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.

Recent studies suggest that bone marrow-derived macrophages can effectively reduce beta-amyloid (Abeta) deposition in brain. To further elucidate the mechanisms by which macrophages degrade Abeta, we cultured murine macrophages on top of Abeta plaque-bearing brain sections from transgenic mice expressing PDAPP [human amyloid precursor protein (APP) with the APP(717V>F) mutation driven by the platelet-derived growth factor promoter]. Using this ex vivo assay, we found that macrophages from wild-type mice very efficiently degrade both soluble and insoluble Abeta in a time-dependent manner and markedly eliminate thioflavine-S positive amyloid deposits. Because macrophages express and secrete apolipoprotein E (apoE), we compared the efficiency of Abeta degradation by macrophages prepared from apoE-deficient mice or mice expressing human apoE2, apoE3, or apoE4. Macrophages expressing apoE2 were more efficient at degrading Abeta than apoE3-expressing, apoE4-expressing, or apoE-deficient macrophages. Moreover, macrophage-induced degradation of Abeta was effectively blocked by an anti-apoE antibody and receptor-associated protein, an antagonist of the low-density lipoprotein (LDL) receptor family, suggesting involvement of LDL receptors. Measurement of matrix metalloproteinase-9 (MMP-9) activity in the media from human apoE-expressing macrophages cocultured with Abeta-containing brain sections revealed greater levels of MMP-9 activity in apoE2-expressing than in either apoE3- or apoE4-expressing macrophages. Differences in MMP-9 activity appear to contribute to the isoform-specific differences in Abeta degradation by macrophages. These apoE isoform-dependent effects of macrophages on Abeta degradation suggest a novel "peripheral" mechanism for Abeta clearance from brain that may also, in part, explain the isoform-dependent effects of apoE in determining the genetic risk for Alzheimer's disease.

Cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases results in generation of the amyloid-beta protein (Abeta), which is characteristically deposited in the brain of Alzheimer's disease patients. Inhibitors of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (the statins) reduce levels of cholesterol and isoprenoids such as geranylgeranyl pyrophosphate (GGPP). Previous studies have demonstrated that cholesterol increases and statins reduce Abeta levels mostly by regulating beta-secretase activity. In this study, we focused on the role of geranylgeranyl isoprenoids GGPP and geranylgeraniol (GGOH) in regulating Abeta production. Our data show that the inhibition of GGPP synthesis by statins plays an important role in statin-mediated reduction of Abeta secretion. Consistent with this finding, the geranylgeranyl isoprenoids preferentially increase the yield of Abeta of 42 residues (Abeta42) in a dose-dependent manner. Our studies further demonstrated that geranylgeranyl isoprenoids increase the yield of APP-CTFgamma (a.k.a. AICD) as well as Abeta by stimulating gamma-secretase-mediated cleavage of APP-CTFalpha and APP-CTFbeta in vitro. Furthermore, GGOH increases the levels of the active gamma-secretase complex in the detergent-insoluble membrane fraction along with its substrates, APP-CTFalpha and APP-CTFbeta. Our results indicate that geranylgeranyl isoprenoids may be an important physiological facilitator of gamma-secretase activity that can foster production of the pathologically important Abeta42.

Naturally occurring antibodies directed against beta-amyloid (Abeta) were detected in intravenous immunoglobulin preparations. After intravenous immunoglobulin treatment in patients with different neurological diseases, total Abeta and Abeta(1-42) in the cerebrospinal fluid was reduced significantly compared with baseline values. In the serum, total Abeta levels increased after intravenous immunoglobulin treatment, whereas no significant change was observed in Abeta(1-42) levels. Antibodies against Abeta were found to be increased in the serum and cerebrospinal fluid after intravenous immunoglobulin treatment. This study provides evidence that intravenous immunoglobulin or purified Abeta antibodies may modify Abeta and Abeta(1-42) levels, suggesting potential utility as a therapy for Alzheimer disease.