action error Mike Mullan | Alzheimer Mullan Research Notes

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Mike Mullan

Anti-Tumoral Activity of a Short Decapeptide Fragment of the Alzheimer's Abeta Peptide.

The inhibition of angiogenesis is regarded as a promising avenue for cancer treatment. Although some antiangiogenic compounds are in the process of development and testing, these often prove ineffective in vivo, therefore the search for new inhibitors is critical. We have recently identified a ten amino acid fragment of the Alzheimer Abeta peptide that is anti-angiogenic both in vitro and in vivo. In the present study, we investigated the antitumoral potential of this decapeptide using human MCF-7 breast carcinoma xenografts nude mice. We observed that this decapeptide was able to suppress MCF-7 tumor growth more potently than the antiestrogen tamoxifen. Inhibition of tumor vascularization as determined by PECAM-1 immunostaining and decreased tumor cell proliferation as determined by Ki67 immunostaining were observed following treatment with the Abeta fragment. In vitro, this peptide had no direct impact on MCF-7 tumor cell proliferation and survival suggesting that the inhibition of tumor growth and tumor cell proliferation observed in vivo is related to the antiangiogenic activity of the peptide. Taken together these data suggest that this short Abeta derivative peptide may constitute a new antitumoral agent.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of beta-amyloid (Abeta) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Abeta peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Abeta peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that Abeta inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Characterization and use of human brain microvascular endothelial cells to examine β-amyloid exchange in the blood-brain barrier. Bachmeier C, Mullan M, Paris D.

Alzheimer's disease (AD) is characterized by excessive cerebrovascular deposition of the β-amyloid peptide (Aβ). The investigation of Aβ transport across the blood-brain barrier (BBB) has been hindered by inherent limitations in the cellular systems currently used to model the BBB, such as insufficient barrier properties and poor reproducibility. In addition, many of the existing models are not of human or brain origin and are often arduous to establish and maintain. Thus, we characterized an in vitro model of the BBB employing human brain microvascular endothelial cells (HBMEC) and evaluated its utility to investigate Aβ exchange at the blood-brain interface. Our HBMEC model offers an ease of culture compared with primary isolated or coculture BBB models and is more representative of the human brain endothelium than many of the cell lines currently used to study the BBB. In our studies, the HBMEC model exhibited barrier properties comparable to existing BBB models as evidenced by the restricted permeability of a known paracellular marker. In addition, using a simple and rapid fluormetric assay, we showed that antagonism of key Aβ transport proteins significantly altered the bi-directional transcytosis of fluorescein-Aβ (1-42) across the HBMEC model. Moreover, the magnitude of these effects was consistent with reports in the literature using the same ligands in existing in vitro models of the BBB. These studies establish the HBMEC as a representative in vitro model of the BBB and offer a rapid fluorometric method of assessing Aβ exchange between the periphery and the brain.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Depletion of CXCR2 inhibits γ-secretase activity and amyloid-β production in a murine model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline. Recent studies from our group and others have suggested that certain G-protein coupled receptors (GPCRs) can influence the processing of the amyloid precursor protein (APP). Earlier, we demonstrated that stimulation of a chemokine receptor, CXCR2, results in enhanced γ-secretase activity and in increased amyloid-beta (Aβ) production. Taken together, results obtained from in vitro studies indicate that therapeutic targeting of CXCR2 might aid in lowering Aβ levels in the AD brain. To better understand the precise function and to predict the consequences of CXCR2 depletion in the AD brain, we have crossed CXCR2 knockout mice with mice expressing presenilin (PS1 M146L) and APPsw mutations (PSAPP). Our present study confirms that CXCR2 depletion results in reduction of Aβ with concurrent increases of γ-secretase substrates. At the mechanistic level, the effect of CXCR2 on γ-secretase was not found to occur via their direct interaction. Furthermore, we provide evidence that Aβ promotes endocytosis of CXCR2 via increasing levels of CXCR2 ligands. In conclusion, our current study confirms the regulatory role of CXCR2 in APP processing, and poses it as a potential target for developing novel therapeutics for intervention in AD.

For more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier.

Several large population-based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. To determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer Aβ peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aβ production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro, whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aβ clearance across the blood-brain barrier (BBB), whereas amlodipine and nifedipine were ineffective showing that the Aβ-lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Aβ burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice, and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity, but rely on their ability to lower brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the BBB.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine.

Venlafaxine and its metabolite desvenlafaxine are serotonin-norepinephrine reuptake inhibitors currently prescribed for the treatment of depression. Previously, it was reported that venlafaxine is an inducer of MDR1, the gene responsible for P-glycoprotein (P-gp). The present study expanded upon these findings by examining the effect of venlafaxine and desvenlafaxine on the expression of both P-gp and the breast cancer resistance protein (BCRP) in human brain endothelial cells (HBMEC), an in vitro model of the blood-brain barrier (BBB). The HBMEC were treated for 1 h with various concentrations (500 nM to 50 µM) of venlafaxine and desvenlafaxine. Western blot analysis revealed treatment with venlafaxine significantly induced the expression of P-gp (2-fold) and BCRP (1.75-fold) in a dose-dependent manner, while treatment with desvenlafaxine had no effect on drug efflux transporter expression. To determine the functional significance of this effect, the permeability of a known drug efflux probe, rhodamine 123, across the BBB model and Caco-2 cells, a model of intestinal absorption, were examined. Treatment with venlafaxine (1-50 µM) for 1 h significantly reduced the apical-to-basolateral permeability of R123 across the BBB model (30%) and Caco-2 cell monolayers (25%), indicative of increased drug efflux transporter expression at the apical membrane. Conversely, desvenlafaxine had no effect on R123 permeability in either cellular model. These studies indicate that venlafaxine, but not desvenlafaxine is an inducer of drug efflux transporter expression, which consequently increases the potential for clinical drug-drug interactions. Therefore, based on these preliminary results, caution should be taken when prescribing venlafaxine with other P-gp substrates.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier.

Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer's disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Feasibility of Predicting MCI/AD Using Neuropsychological Tests and Serum β-Amyloid.

We examined the usefulness of brief neuropsychological tests and serum Aβ as a predictive test for detecting MCI/AD in older adults. Serum Aβ levels were measured from 208 subjects who were cognitively normal at enrollment and blood draw. Twenty-eight of the subjects subsequently developed MCI (n = 18) or AD (n = 10) over the follow-up period. Baseline measures of global cognition, memory, language fluency, and serum Aβ(1-42) and the ratio of serum Aβ(1-42)/Aβ(1-40) were significant predictors for future MCI/AD using Cox regression with demographic variables, APOE ε4, vascular risk factors, and specific medication as covariates. An optimal sensitivity of 85.2% and specificity of 86.5% for predicting MCI/AD was achieved using ROC analyses. Brief neuropsychological tests and measurements of Aβ(1-42) obtained via blood warrants further study as a practical and cost effective method for wide-scale screening for identifying older adults who may be at-risk for pathological cognitive decline.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism.

Alzheimer’s disease (AD) is characterized by the brain accumulation of Aβ peptides and by the presence of neurofibrillary tangles. Aβ is believed to play an important role in AD and it has been shown that certain flavonoids can affect Aβ production. Recently, it was suggested that the Aβ lowering properties of flavonoids are mediated by a direct inhibition the β-secretase (BACE-1) activity, the rate limiting enzyme responsible for the production of Aβ peptides. Westernblots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein processing and Aβ production. A cell free chemoluminescent assay using human recombinant BACE-1 was used to assess the effect of flavonoids on BACE-1 activity. The effect of flavonoids on NFκB activation was determined by using a stable NFκB luciferase reporter cell line. Molecular docking simulations were performed to predict the binding of flavonoids to the BACE-1 catalytic site. Real time quantitative PCR was used to determine the effect of flavonoids on BACE-1 transcription. We show in a cell free assay that flavonoids are only weak inhibitors of BACE-1 activity. Docking simulation studies with different BACE-1 structures also suggest that flavonoids are poor BACE-1 inhibitors as they appear to adopt various docking poses in the active site pocket and have weak docking scores that differ as a function of the BACE-1 structures studied. Moreover, a weak correlation was observed between the effect of flavonoids on Aβ production in vitro and their ability to lower BACE-1 activity suggesting that the Aβ lowering properties of flavonoids in whole cells are not mediated via direct inhibition of BACE-1 activity. We found however a strong correlation between the inhibition of NFκB activation by flavonoids and their Aβ lowering properties suggesting that flavonoids inhibit Aβ production in whole cells via NFκB related mechanisms. As NFκB has been shown to regulate BACE-1 expression, we show that NFκB lowering flavonoids inhibit BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids inhibit Aβ and sAPPβ production by regulating BACE-1 expression and not by directly inhibiting BACE-1 activity.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

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