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Article: Intranasal neprilysin rapidly eliminates amyloid-beta plaques, but causes plaque compensations: the explanation why the amyloid-beta cascade may fail?

Humpel, Christian

2022 Volume 17, Issue 9, Page(s) 1881–1884

Abstract: Neurodegenerative brain disorders are a major burden in our society, such as Alzheimer´s disease. In order to repair or prevent such diseases, drugs are designed which enter the brain, but the blood-brain barrier limits their entry and the search for ... ...

Abstract	Neurodegenerative brain disorders are a major burden in our society, such as Alzheimer´s disease. In order to repair or prevent such diseases, drugs are designed which enter the brain, but the blood-brain barrier limits their entry and the search for alternative pathways is important. Recently, we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice. This review describes the anatomical structure of the intranasal pathway, explains the intranasal delivery of pure neprilysin, cell-loaded neprilysin (platelets) and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.
Language	English
Publishing date	2022-02-10
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.335138
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Biomaterials in neuronal repair.

Humpel, Christian

Neurochemistry international

2021 Volume 147, Page(s) 105063

MeSH term(s)	Animals ; Biocompatible Materials ; Humans ; Neurons/metabolism
Chemical Substances	Biocompatible Materials
Language	English
Publishing date	2021-04-30
Publishing country	England
Document type	Editorial
ZDB-ID	283190-9
ISSN	1872-9754 ; 0197-0186
ISSN (online)	1872-9754
ISSN	0197-0186
DOI	10.1016/j.neuint.2021.105063
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Zs.A 1610: Show issues

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Article ; Online: A Combination of Heavy Metals and Intracellular Pathway Modulators Induces Alzheimer Disease-like Pathologies in Organotypic Brain Slices.

Korde, Dhwani S / Humpel, Christian

Biomolecules

2024 Volume 14, Issue 2

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFT). Modelling aspects of AD is challenging due to its complex multifactorial etiology and pathology. ...

Abstract	Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFT). Modelling aspects of AD is challenging due to its complex multifactorial etiology and pathology. The present study aims to establish a cost-effective and rapid method to model the two primary pathologies in organotypic brain slices. Coronal hippocampal brain slices (150 µm) were generated from postnatal (day 8-10) C57BL6 wild-type mice and cultured for 9 weeks. Collagen hydrogels containing either an empty load or a mixture of human Aβ42 and P301S aggregated tau were applied to the slices. The media was further supplemented with various intracellular pathway modulators or heavy metals to augment the appearance of Aβ plaques and tau NFTs, as assessed by immunohistochemistry. Immunoreactivity for Aβ and tau was significantly increased in the ventral areas in slices with a mixture of human Aβ42 and P301S aggregated tau compared to slices with empty hydrogels. Aβ plaque- and tau NFT-like pathologies could be induced independently in slices. Heavy metals (aluminum, lead, cadmium) potently augmented Aβ plaque-like pathology, which developed intracellularly prior to cell death. Intracellular pathway modulators (scopolamine, wortmannin, MHY1485) significantly boosted tau NFT-like pathologies. A combination of nanomolar concentrations of scopolamine, wortmannin, MHY1485, lead, and cadmium in the media strongly increased Aβ plaque- and tau NFT-like immunoreactivity in ventral areas compared to the slices with non-supplemented media. The results highlight that we could harness the potential of the collagen hydrogel-based spreading of human Aβ42 and P301S aggregated tau, along with pharmacological manipulation, to produce pathologies relevant to AD. The results offer a novel ex vivo organotypic slice model to investigate AD pathologies with potential applications for screening drugs or therapies in the future.
MeSH term(s)	Mice ; Animals ; Humans ; Alzheimer Disease/metabolism ; tau Proteins/metabolism ; Cadmium/metabolism ; Wortmannin/metabolism ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Neurofibrillary Tangles/metabolism ; Neurofibrillary Tangles/pathology ; Brain/metabolism ; Plaque, Amyloid/complications ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology ; Collagen/metabolism ; Hydrogels/metabolism ; Scopolamine Derivatives/metabolism
Chemical Substances	tau Proteins ; Cadmium (00BH33GNGH) ; Wortmannin (XVA4O219QW) ; Amyloid beta-Peptides ; Collagen (9007-34-5) ; Hydrogels ; Scopolamine Derivatives
Language	English
Publishing date	2024-01-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom14020165
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Article: NGF Released from Blood Cells or Collagen Hydrogels as a Therapeutic Target in Alzheimer's Disease?

Humpel, Christian

Advances in experimental medicine and biology

2021 Volume 1331, Page(s) 193–202

Abstract: Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain characterized by extracellular beta-amyloid plaques, intraneuronal tau inclusions, vascular impairment, inflammation, neurodegeneration, and memory loss. Acetylcholine is the ... ...

Abstract	Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain characterized by extracellular beta-amyloid plaques, intraneuronal tau inclusions, vascular impairment, inflammation, neurodegeneration, and memory loss. Acetylcholine is the most important neurotransmitter for memory, and cholinergic neurons selectively degenerate in AD, and a loss of acetylcholine directly correlates with cognitive decline. Nerve growth factor (NGF) is the most potent growth factor to support the survival of these cholinergic neurons. Thus, researchers are interested to deliver NGF directly into the brain to the cholinergic neurons. As the brain is isolated by the blood-brain barrier, the large protein NGF cannot easily pass into the brain, and peripheral administration of NGF also causes severe side effects. Blood cells may represent a potent therapeutic strategy to deliver NGF into the brain. Monocytes can be isolated and loaded with NGF and may transmigrate into the brain. As monocytes are precursors of microglia, they may differentiate and release NGF but also phagocyte and eliminate toxic plaques. Platelets are small anuclear cells and become rapidly activated during vascular lesions, and they may migrate to lesion sites and repair blood vessels and also eliminate toxic beta-amyloid depositions in vessels. In order to guarantee a stable and slow release, the use of biomaterials is of interest, especially collagen hydrogels that may be useful to protect these transmigrating blood cells. In this review, I summarize advantages and challenges of using transmigrating cells to deliver NGF directly into the brain.
MeSH term(s)	Alzheimer Disease/drug therapy ; Collagen ; Humans ; Hydrogels ; Monocytes ; Nerve Growth Factor
Chemical Substances	Hydrogels ; Collagen (9007-34-5) ; Nerve Growth Factor (9061-61-4)
Language	English
Publishing date	2021-08-28
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-74046-7_12
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Article: Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model.

Humpel, Christian

Frontiers in aging neuroscience

2021 Volume 13, Page(s) 649646

Abstract: Alzheimer's disease (AD) is pathologically characterized by extracellular beta-amyloid (Aβ) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these Aβ plaques and the Aβ-degrading enzyme neprilysin is a ... ...

Abstract	Alzheimer's disease (AD) is pathologically characterized by extracellular beta-amyloid (Aβ) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these Aβ plaques and the Aβ-degrading enzyme neprilysin is a potent drug to degrade plaques. The major challenge is to deliver bioactive neprilysin into the brain via the blood-brain barrier. The aim of the present study is to explore if intranasal delivery of neprilysin can eliminate plaques in a transgenic AD mouse model (APP_SweDI). We will test if collagen or platelets are useful vehicles to deliver neprilysin into the brain. Using organotypic brain slices from adult transgenic APP_SweDI mice, we show that neprilysin alone or loaded in collagen hydrogels or in platelets cleared cortical plaques. Intransasal delivery of neprilysin alone increased small Aβ depositions in the middle and caudal cortex in transgenic mice. Platelets loaded with neprilysin cleared plaques in the frontal cortex after intranasal application. Intranasal delivery of collagen-loaded neprilysin was very potent to clear plaques especially in the middle and caudal parts of the cortex. Our data support that the Aβ degrading enzyme neprilysin delivered to the mouse brain can clear Aβ plaques and intranasal delivery (especially with collagen as a vehicle) is a fast and easy application. However, it must be considered that intranasal neprilysin may also activate more plaque production in the transgenic mouse brain as a side effect.
Language	English
Publishing date	2021-04-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.649646
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Article: Saliva: a challenging human fluid to diagnose brain disorders with a focus on Alzheimer's disease.

Zürcher, Christine / Humpel, Christian

Neural regeneration research

2023 Volume 18, Issue 12, Page(s) 2606–2610

Abstract: Biomarkers are molecules of biological processes that help in both the diagnosis of human diseases and in follow-up assessments of therapeutic responses. Biomarkers can be measured in many human fluids, such as blood, cerebrospinal fluid, urine, and ... ...

Abstract	Biomarkers are molecules of biological processes that help in both the diagnosis of human diseases and in follow-up assessments of therapeutic responses. Biomarkers can be measured in many human fluids, such as blood, cerebrospinal fluid, urine, and saliva. The -omics methods (genomics, RNomics, proteomics, and metabolomics) are useful at measuring thousands of markers in a small volume. Saliva is a human fluid that is easily accessible, without any ethical concerns. Yet, saliva remains unexplored in regard to many human disease biomarkers. In this review, we will give an overview on saliva and how it can be influenced by exogenous factors. As we focus on the potential use of saliva as a diagnostic tool in brain disorders (especially Alzheimer's disease), we will cover how saliva is linked to the brain. We will discuss that saliva is a heterogeneous human fluid, yet useful for the discovery of biomarkers in human disorders. However, a procedure and consensus that is controlled, validated, and standardized for the collection and processing of saliva is required, followed by a highly sensitive diagnostic approach.
Language	English
Publishing date	2023-07-14
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.373675
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Article ; Online: Long-term organotypic brain slices cultured on collagen-based microcontact prints: A perspective for a brain-on-a-chip.

Steiner, Katharina / Humpel, Christian

Journal of neuroscience methods

2023 Volume 399, Page(s) 109979

Abstract: Organotypic brain slices are three-dimensional 150 µm-thick sections of a postnatal day 10 mouse and can be cultured for several weeks in vitro. In such brain slices the complex cellular connections are preserved with a high viability. These brain slices ...

Abstract	Organotypic brain slices are three-dimensional 150 µm-thick sections of a postnatal day 10 mouse and can be cultured for several weeks in vitro. In such brain slices the complex cellular connections are preserved with a high viability. These brain slices can be connected to collagen-loaded microcontact prints to develop a simple brain-on-a-chip model. Using the microcontact printing technique, many peptides or proteins can be printed onto a semipermeable membrane and linked to brain slices. On these microcontact prints, brain-derived nerve fibers grow out, or microglia can get activated and migrate out, or also new brain vessels can be formed. Such a brain-on-a-chip model may allow to develop new drugs or a diagnostic method for neurodegenerative diseases.
MeSH term(s)	Animals ; Mice ; Brain/metabolism ; Collagen/metabolism ; Microglia/metabolism ; Lab-On-A-Chip Devices
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2023-09-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2023.109979
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Article ; Online: Beta-Amyloid Enhances Vessel Formation in Organotypic Brain Slices Connected to Microcontact Prints.

Steiner, Katharina / Humpel, Christian

Biomolecules

2023 Volume 14, Issue 1

Abstract: In Alzheimer's disease, the blood-brain barrier breakdown, blood vessel damage and re-organization are early events. Deposits of the small toxic peptide beta-amyloid (Aβ) cause the formation of extracellular plaques and accumulate in vessels disrupting ... ...

Abstract	In Alzheimer's disease, the blood-brain barrier breakdown, blood vessel damage and re-organization are early events. Deposits of the small toxic peptide beta-amyloid (Aβ) cause the formation of extracellular plaques and accumulate in vessels disrupting the blood flow but may also play a role in blood clotting. In the present study, we aim to explore the impact of Aβ on the migration of endothelial cells and subsequent vessel formation. We use organotypic brain slices of postnatal day 10 wildtype mice (C57BL/6) and connect them to small microcontact prints (µCPs) of collagen. Our data show that laminin-positive endothelial cells migrate onto collagen µCPs, but without any vessel formation after 4 weeks. When the µCPs are loaded with human Aβ40, (aggregated) human Aβ42 and mouse Aβ42 peptides, the number and migration distance of endothelial cells are significantly reduced, but with a more pronounced subsequent vessel formation. The vessel formation is verified by zonula occludens (ZO)-1 and -2 stainings and confocal microscopy. In addition, the vessel formation is accompanied by a stronger GFAP-positive astroglial formation. Finally, we show that vessels can grow towards convergence when two opposed slices are connected via microcontact-printed lanes. In conclusion, our data show that Aβ promotes vessel formation, and organotypic brain slices connected to collagen µCPs provide a potent tool to study vessel formation.
MeSH term(s)	Mice ; Humans ; Animals ; Endothelial Cells/metabolism ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Alzheimer Disease/metabolism ; Collagen/metabolism ; Peptide Fragments/pharmacology ; Peptide Fragments/metabolism
Chemical Substances	Amyloid beta-Peptides ; Collagen (9007-34-5) ; Peptide Fragments
Language	English
Publishing date	2023-12-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom14010003
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Article ; Online: Organotypic Brain Slices of ADULT Transgenic Mice: A Tool to Study Alzheimer's Disease.

Humpel, Christian

Current Alzheimer research

2018 Volume 16, Issue 2, Page(s) 172–181

Abstract: Transgenic mice have been extensively used to study the Alzheimer pathology. In order to reduce, refine and replace (3Rs) the number of animals, ex vivo cultures are used and optimized. Organotypic brain slices are the most potent ex vivo slice culture ... ...

Abstract	Transgenic mice have been extensively used to study the Alzheimer pathology. In order to reduce, refine and replace (3Rs) the number of animals, ex vivo cultures are used and optimized. Organotypic brain slices are the most potent ex vivo slice culture models, keeping the 3-dimensional structure of the brain and being closest to the in vivo situation. Organotypic brain slice cultures have been used for many decades but were mainly prepared from postnatal (day 8-10) old rats or mice. More recent work (including our lab) now aims to culture organotypic brain slices from adult mice including transgenic mice. Especially in Alzheimer´s disease research, brain slices from adult transgenic mice will be useful to study beta-amyloid plaques, tau pathology and glial activation. This review will summarize the studies using organotypic brain slice cultures from adult mice to mimic Alzheimer's disease and will highlight advantages and also pitfalls using this technique.
MeSH term(s)	Aging ; Alzheimer Disease/pathology ; Alzheimer Disease/physiopathology ; Animals ; Brain/pathology ; Brain/physiopathology ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Tissue Culture Techniques/methods
Language	English
Publishing date	2018-12-12
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2205170-3
ISSN	1875-5828 ; 1567-2050
ISSN (online)	1875-5828
ISSN	1567-2050
DOI	10.2174/1567205016666181212153138
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Article ; Online: Organotypic Brain Slice Cultures.

Humpel, Christian

Current protocols in immunology

2018 Volume 123, Issue 1, Page(s) e59

Abstract: Ex vivo cell culture models are of particular interest for neurobiologists, as these allow the study of brain cells in an isolated environment. Organotypic brain slice cultures allow growth of three-dimensional brain tissue that conserves the cellular ... ...

Abstract	Ex vivo cell culture models are of particular interest for neurobiologists, as these allow the study of brain cells in an isolated environment. Organotypic brain slice cultures allow growth of three-dimensional brain tissue that conserves the cellular architecture. This unit describes the preparation and culturing of organotypic brain slices from mice. In three basic protocols, the general procedure, the specific preparation of chopper slices, and slicing of whole-brain vibratome sections are described. Support protocols explain the use of postnatal or adult mice, the preparation of coronal or sagittal slices, the preparation of co-cultures, post-processing of slices, the use of extra filter membranes, and the re-use of membrane inserts. This unit provides an easy-to-understand methodological introduction to brain slice cultures. © 2018 by John Wiley & Sons, Inc.
MeSH term(s)	Animals ; Animals, Newborn ; Brain/cytology ; Brain/metabolism ; Mice ; Microdissection/methods ; Organ Culture Techniques/methods
Language	English
Publishing date	2018-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1934-368X
ISSN (online)	1934-368X
DOI	10.1002/cpim.59
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