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Article

Time to forget mice? Using human cells for drug testing? (2016)

Windisch, Manfred

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Language: English

In: Neurobiology of Aging, March 2016, Vol.39, pp.S9-S9

Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.neurobiolaging.2016.01.047 Byline: Manfred Windisch Author Affiliation: NeuroScios GmbH, St. Radegund, Austria

Keywords: Anatomy & Physiology

ISSN: 0197-4580

E-ISSN: 1558-1497

DOI: 10.1016/j.neurobiolaging.2016.01.047

URL: View record in ScienceDirect (Access to full text may be restricted)

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MOUSE MODELS OF ALZHEIMER'S DISEASE: PROMISE, PROBLEMS, AND PREMISES (2014)

Windisch, Manfred

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Language: English

In: Alzheimer's & Dementia: The Journal of the Alzheimer's Association, July 2014, Vol.10(4), pp.P478-P478

Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jalz.2014.05.695 Byline: Manfred Windisch Author Affiliation: Psychogenics, Tarrytown, New York, United States Article Note: (miscellaneous) P2-022

Keywords: Alzheimer'S Disease – Models;

ISSN: 1552-5260

E-ISSN: 1552-5279

DOI: 10.1016/j.jalz.2014.05.695

URL: View record in ScienceDirect (Access to full text may be restricted)

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3

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86 Animal models for preclinical testing of early AD? (2012)

Windisch, Manfred

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Language: English

In: Neurobiology of Aging, May 2012, Vol.33, pp.S37-S37

Keywords: Anatomy & Physiology

ISSN: 0197-4580

E-ISSN: 1558-1497

DOI: 10.1016/j.neurobiolaging.2012.01.104

Source: ScienceDirect Journals (Elsevier)

URL: View record in ScienceDirect (Access to full text may be restricted)

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4

Article

We Can Treat Alzheimer's Disease Successfully in Mice but Not in Men: Failure in Translation? A Perspective (2014)

Windisch, Manfred

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Language: English

In: Neurodegenerative Diseases, January 2014, Vol.13(2-3), pp.147-150

Description: Background: Animal models closely resembling the etiopathogenesis of Alzheimer's disease (AD) are needed for research on disease mechanisms and for drug development. No natural model of AD is available, so big hopes arose from transgenic and knockout technology, expecting that modulation and expression of pathogenetically important proteins resemble human brain pathology and functional deficits in the expected morphological and temporal pattern. Objective: The real usefulness of these models should be discussed from an objective point of view. Results: Not a single one of the published transgenic rodent models fulfils this hope, and even complex multiple transgenic animals do not suffer from real AD. It is crucial to be aware that all of the commonly used mice and rats are just models, and therefore results from drug efficacy testing have to be interpreted with care. Repeated experience with failed trials of new treatments that previously had been published as successful in animals has led to the wrong conclusion that animal models are of low predictive value or even of no use. Often clinical trials replicate exactly what was shown in the animal proof-of-concept studies. Conclusion: The value of animal models depends mainly on the careful experimentation and correct interpretation of results. Appropriate planning of experiments will help to increase the predictive value in drug development programs, though this may also increase negative findings. However, the early failure may enable a faster focus on more promising strategies.

Keywords: Further Section ; Tau Protein ; Translational Methods ; Transgenic Technology ; Pathology ; Behavior ; Amyloid-Β ; Medicine

ISBN: 9783318025118

ISBN: 3318025119

ISSN: 1660-2854

E-ISSN: 1660-2862

DOI: 10.1159/000357568

URL: view record in Karger (Access to full text may be restricted)

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5

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Why did animal models fail to show the right way to Alzheimer Therapy? (2014)

Windisch, Manfred

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Language: English

In: Neurobiology of Aging, March 2014, Vol.35, pp.S25-S26

Keywords: Anatomy & Physiology

ISSN: 0197-4580

E-ISSN: 1558-1497

DOI: 10.1016/j.neurobiolaging.2014.01.127

Source: ScienceDirect Journals (Elsevier)

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6

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Non-selective calcium channel blocker bepridil decreases secondary pathology in mice after photothrombotic cortical lesion (2013)

Anu Lipsanen ; Stefanie Flunkert ; Kristina Kuptsova ; [et al.]

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Language: English

In: PLoS ONE, 01 January 2013, Vol.8(3), p.e60235

Description: Experimental studies have identified a complex link between neurodegeneration, β-amyloid (Aβ) and calcium homeostasis. Here we asked whether early phase β-amyloid pathology in transgenic hAPPSL mice exaggerates the ischemic lesion and remote secondary pathology in the thalamus, and whether a non-selective calcium channel blocker reduces these pathologies. Transgenic hAPPSL (n = 33) and non-transgenic (n = 30) male mice (4-5 months) were subjected to unilateral cortical photothrombosis and treated with the non-selective calcium channel blocker bepridil (50 mg/kg, p.o., once a day) or vehicle for 28 days, starting administration 2 days after the operation. Animals were then perfused for histological analysis of infarct size, Aβ and calcium accumulation in the thalamus. Cortical photothrombosis resulted in a small infarct, which was associated with atypical Aβ and calcium accumulation in the ipsilateral thalamus. Transgenic mice had significantly smaller infarct volumes than non-transgenic littermates (P〈0.05) and ischemia-induced rodent Aβ accumulation in the thalamus was lower in transgenic mice compared to non-transgenic mice (P〈0.01). Bepridil decreased calcium load in the thalamus (P〈0.01). The present data suggest less pronounced primary and secondary pathology in hAPPSL transgenic mice after ischemic cortical injury. Bepridil particularly decreased calcium pathology in the thalamus following ischemia.

Keywords: Sciences (General)

E-ISSN: 1932-6203

DOI: 10.1371/journal.pone.0060235

URL: View full text in DOAJ

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7

Article

Tracking of magnetite labeled nanoparticles in the rat brain using MRI (2014)

Naira P Martínez Vera ; Reinhold Schmidt ; Klaus Langer ; [et al.]

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Language: English

In: PLoS ONE, 01 January 2014, Vol.9(3), p.e92068

Description: This study was performed to explore the feasibility of tracing nanoparticles for drug transport in the healthy rat brain with a clinical MRI scanner. Phantom studies were performed to assess the R1 ( = 1/T1) relaxivity of different magnetically labeled nanoparticle (MLNP) formulations that were based on biodegradable human serum albumin and that were labeled with magnetite of different size. In vivo MRI measurements in 26 rats were done at 3T to study the effect and dynamics of MLNP uptake in the rat brain and body. In the brain, MLNPs induced T1 changes were quantitatively assessed by T1 relaxation time mapping in vivo and compared to post-mortem results from fluorescence imaging. Following intravenous injection of MLNPs, a visible MLNP uptake was seen in the liver and spleen while no visual effect was seen in the brain. However a histogram analysis of T1 changes in the brain demonstrated global and diffuse presence of MLNPs. The magnitude of these T1 changes scaled with post-mortem fluorescence intensity. This study demonstrates the feasibility of tracking even small amounts of magnetite labeled NPs with a sensitive histogram technique in the brain of a living rodent.

Keywords: Sciences (General)

E-ISSN: 1932-6203

DOI: 10.1371/journal.pone.0092068

URL: View full text in DOAJ

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8

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Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits.(Research Article) (2014)

Izzo, Nicholas J. ; Staniszewski, Agnes ; To, Lillian ; [et al.]

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Language: English

In: PLoS ONE, Nov 12, 2014, Vol.9(11)

Description: Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC.sub.50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

Keywords: Brain -- Chemical Properties ; Brain -- Analysis ; Neurons -- Chemical Properties ; Neurons -- Analysis ; Genetic Engineering -- Chemical Properties ; Genetic Engineering -- Analysis ; Oligomers -- Chemical Properties ; Oligomers -- Analysis ; Alzheimer'S Disease -- Chemical Properties ; Alzheimer'S Disease -- Analysis

ISSN: 1932-6203

DOI: 10.1371/journal.pone.0111898

Source: Cengage Learning, Inc.

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9

Article

Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans (2017)

Laczó, Jan ; Markova, Hana ; Lobellova, Veronika ; [et al.]

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Language: English

In: Psychopharmacology, 2017, Vol.234(4), pp.535-547

Description: Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. Objectives We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. Methods We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. Results Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. Conclusions In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.

Keywords: Spatial orientation ; Scopolamine ; Acetylcholinesterase inhibitor ; Human ; Rat

ISSN: 0033-3158

E-ISSN: 1432-2072

DOI: 10.1007/s00213-016-4488-2

URL: View full text in Springer (Subscribers only)

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10

Article

BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains (2018)

Mirsada Causevic ; Kristina Dominko ; Martina Malnar ; [et al.]

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Language: English

In: PLoS ONE, 01 January 2018, Vol.13(7), p.e0200344

Description: It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer's disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1-null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1-cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4-weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1-proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease.

Keywords: Sciences (General)

E-ISSN: 1932-6203

DOI: 10.1371/journal.pone.0200344

URL: View full text in DOAJ

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Kooperativer Bibliotheksverbund

Berlin Brandenburg