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  1. Article ; Online: 442 Repurposing FDA-approved PI3K/Akt Inhibitors to Improve Anti-Cancer Drug Brain Uptake in Glioblastoma Resection Models

    Louis Rodgers / Yuma Tega / Julia A. Schulz / Anika M.S. Hartz / Bjoern Bauer

    Journal of Clinical and Translational Science, Vol 6, Pp 87-

    2022  Volume 87

    Abstract: OBJECTIVES/GOALS: We have shown that glioblastoma upregulates blood-brain barrier drug efflux transporters via a mechanism that likely involves TNFα and PI3K/Akt. Our goal is to repurpose FDA-approved PI3K/Akt inhibitors to increase anticancer drug ... ...

    Abstract OBJECTIVES/GOALS: We have shown that glioblastoma upregulates blood-brain barrier drug efflux transporters via a mechanism that likely involves TNFα and PI3K/Akt. Our goal is to repurpose FDA-approved PI3K/Akt inhibitors to increase anticancer drug brain concentrations, which holds the potential for translation into the neuro-oncology clinic. METHODS/STUDY POPULATION: GL261 Red-FLuc and MBR525-1 Red-FLuc cells (2μl; 2.5K cells/μl; 1μl/min) were injected into the right hemisphere of 8-week old female J:NU mice (coordinates relative to bregma: AP -2 mm, ML -2 mm, DV -3 mm). Tumor burden was assessed weekly with IVIS® Spectrum in vivo imaging; tumor volume and invasiveness were measured by MRI and histopathology, respectively. On day 14 post-injection, mice received 5-ALA (200 mg/kg ip), and tumors were resected with a 2 mm punch biopsy tool and surgical fluorescence microscope (ex/em: 405/635nm). Drug efflux transporter expression and activity in isolated brain capillaries were determined by Western blot and substrate fluorescence assays, respectively. Cytotoxicity was assessed after 48-hour drug incubation using CyQuant MTT Cell Proliferation Assay kits. RESULTS/ANTICIPATED RESULTS: IC50 values of temozolomide, lapatinib, alpelisib, and miltefosine were N/A, 32, 20, and 190 μM for GL261 Red-FLuc cells and N/A, 49, 36, and 148 μM for MBR525-1 Red-FLuc cells, respectively. Median survival of GL261 Red-FLuc mice was 26.5d and significantly increased to 34d with resection (p=0.116). In GBM mice, drug efflux transporter expression and activity levels in brain capillaries isolated from the contralateral hemisphere were significantly upregulated compared to sham controls. Furthermore, treatment with FDA-approved PI3K/Akt inhibitors, alpelisib and miltefosine, significantly reduced drug efflux transporter expression and activity to control levels. In PK and survival studies, we expect that PI3K/Akt inhibition will increase brain uptake of anticancer drugs and prolong GBM mouse survival. DISCUSSION/SIGNIFICANCE: We ...
    Keywords Medicine ; R
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Cambridge University Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: New Evidence for P-gp-Mediated Export of Amyloid-β PEPTIDES in Molecular, Blood-Brain Barrier and Neuronal Models

    Amanda B. Chai / Anika M. S. Hartz / Xuexin Gao / Alryel Yang / Richard Callaghan / Ingrid C. Gelissen

    International Journal of Molecular Sciences, Vol 22, Iss 246, p

    2021  Volume 246

    Abstract: Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated ... ...

    Abstract Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ 40 and Aβ 42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ 42 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aβ 40 and Aβ 42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aβ out of the brain in Alzheimer’s disease.
    Keywords P-glycoprotein ; ABCB1 ; amyloid-beta ; neuron ; SK-N-SH ; Alzheimer’s disease ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: ABC Transporters and the Alzheimer’s Disease Enigma

    AnikaM.S.Hartz

    Frontiers in Psychiatry, Vol

    2012  Volume 3

    Abstract: Alzheimer’s disease (AD) is considered the “disease of the 21st century”. With a 10-fold increase in global incidence over the past 100 years, AD is now reaching epidemic proportions and by all projections, AD patient numbers will continue to rise. ... ...

    Abstract Alzheimer’s disease (AD) is considered the “disease of the 21st century”. With a 10-fold increase in global incidence over the past 100 years, AD is now reaching epidemic proportions and by all projections, AD patient numbers will continue to rise. Despite intense research efforts, AD remains a mystery and effective therapies are still unavailable. This represents an unmet need resulting in clinical, social, and economic problems. Over the last decade, a new AD research focus has emerged: ATP-binding cassette (ABC) transporters. In this article, we provide an overview of the ABC transporters ABCA1, ABCA2, P-glycoprotein (ABCB1), Mrp1 (ABCC1) and BCRP (ABCG2), all of which are expressed in the brain and have been implicated in AD. We summarize recent findings on the role of these five transporters in AD, and discuss their potential to serve as therapeutic targets.
    Keywords Blood-Brain Barrier ; P-Glycoprotein ; Alzheimer’s disease ; ABC transporter ; ABCA1 ; ABCA2 ; Mrp1 ; BCRP ; Psychiatry ; RC435-571 ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2012-06-01T00:00:00Z
    Publisher Frontiers
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: A Comprehensive Behavioral Test Battery to Assess Learning and Memory in 129S6/Tg2576 Mice.

    Andrea Wolf / Björn Bauer / Erin L Abner / Tal Ashkenazy-Frolinger / Anika M S Hartz

    PLoS ONE, Vol 11, Iss 1, p e

    2016  Volume 0147733

    Abstract: Transgenic Tg2576 mice overexpressing human amyloid precursor protein (hAPP) are a widely used Alzheimer's disease (AD) mouse model to evaluate treatment effects on amyloid beta (Aβ) pathology and cognition. Tg2576 mice on a B6;SJL background strain ... ...

    Abstract Transgenic Tg2576 mice overexpressing human amyloid precursor protein (hAPP) are a widely used Alzheimer's disease (AD) mouse model to evaluate treatment effects on amyloid beta (Aβ) pathology and cognition. Tg2576 mice on a B6;SJL background strain carry a recessive rd1 mutation that leads to early retinal degeneration and visual impairment in homozygous carriers. This can impair performance in behavioral tests that rely on visual cues, and thus, affect study results. Therefore, B6;SJL/Tg2576 mice were systematically backcrossed with 129S6/SvEvTac mice resulting in 129S6/Tg2576 mice that lack the rd1 mutation. 129S6/Tg2576 mice do not develop retinal degeneration but still show Aβ accumulation in the brain that is comparable to the original B6;SJL/Tg2576 mouse. However, comprehensive studies on cognitive decline in 129S6/Tg2576 mice are limited. In this study, we used two dementia mouse models on a 129S6 background--scopolamine-treated 129S6/SvEvTac mice (3-5 month-old) and transgenic 129S6/Tg2576 mice (11-13 month-old)-to establish a behavioral test battery for assessing learning and memory. The test battery consisted of five tests to evaluate different aspects of cognitive impairment: a Y-Maze forced alternation task, a novel object recognition test, the Morris water maze, the radial arm water maze, and a Y-maze spontaneous alternation task. We first established this behavioral test battery with the scopolamine-induced dementia model using 129S6/SvEvTac mice and then evaluated 129S6/Tg2576 mice using the same testing protocol. Both models showed distinctive patterns of cognitive impairment. Together, the non-invasive behavioral test battery presented here allows detecting cognitive impairment in scopolamine-treated 129S6/SvEvTac mice and in transgenic 129S6/Tg2576 mice. Due to the modular nature of this test battery, more behavioral tests, e.g. invasive assays to gain additional cognitive information, can easily be added.
    Keywords Medicine ; R ; Science ; Q
    Subject code 150 ; 616
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice

    David Ma / Amy C. Wang / Ishita Parikh / Stefan J. Green / Jared D. Hoffman / George Chlipala / M. Paul Murphy / Brent S. Sokola / Björn Bauer / Anika M. S. Hartz / Ai-Ling Lin

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Volume 10

    Abstract: Abstract Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut ... ...

    Abstract Abstract Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12–14 weeks old). Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer’s disease (AD). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. KD also increased the relative abundance of putatively beneficial gut microbiota (Akkermansia muciniphila and Lactobacillus), and reduced that of putatively pro-inflammatory taxa (Desulfovibrio and Turicibacter). We also observed that KD reduced blood glucose levels and body weight, and increased blood ketone levels, which might be associated with gut microbiome alteration. Our findings suggest that KD intervention started in the early stage may enhance brain vascular function, increase beneficial gut microbiota, improve metabolic profile, and reduce risk for AD.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

    Shon A. Koren / Matthew J. Hamm / Ryan Cloyd / Sarah N. Fontaine / Emad Chishti / Chiara Lanzillotta / Jennifer Rodriguez-Rivera / Alexandria Ingram / Michelle Bell / Sara M. Galvis-Escobar / Nicholas Zulia / Fabio Di Domenico / Duc Duong / Nicholas T. Seyfried / David Powell / Moriel Vandsburger / Tal Frolinger / Anika M. S. Hartz / John Koren /
    Jeffrey M. Axten / Nicholas J. Laping / Jose F. Abisambra

    International Journal of Molecular Sciences, Vol 22, Iss 3, p

    2021  Volume 1186

    Abstract: Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is ... ...

    Abstract Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.
    Keywords tau ; GSK2606414 ; kinases ; MEMRI ; TMT proteomics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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