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Article ; Online: Microglial roles in Alzheimer's disease: An agent-based model to elucidate microglial spatiotemporal response to beta-amyloid.

Weathered, Catherine / Bardehle, Sophia / Yoon, Choya / Kumar, Niyanta / Leyns, Cheryl E G / Kennedy, Matthew E / Bloomingdale, Peter / Pienaar, Elsje

CPT: pharmacometrics & systems pharmacology

2024 Volume 13, Issue 3, Page(s) 449–463

Abstract: Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In ... ...

Abstract	Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia are innate phagocytotic immune cells that transition into a neuroprotective state and form barriers around plaques. We seek to understand the role of microglia in modifying Aβ dynamics and barrier formation. To quantify the influence of individual microglia behaviors (activation, chemotaxis, phagocytosis, and proliferation) on plaque size and barrier coverage, we developed an agent-based model to characterize the spatiotemporal interactions between microglia and Aβ. Our model qualitatively reproduces mouse data trends where the fraction of microglia coverage decreases as plaques become larger. In our model, the time to microglial arrival at the plaque boundary is significantly negatively correlated (p < 0.0001) with plaque size, indicating the importance of the time to microglial activation for regulating plaque size. In addition, in silico behavioral knockout simulations show that phagocytosis knockouts have the strongest impact on plaque size, but modest impacts on microglial coverage and activation. In contrast, the chemotaxis knockouts had a strong impact on microglial coverage with a more modest impact on plaque volume and microglial activation. These simulations suggest that phagocytosis, chemotaxis, and replication of activated microglia have complex impacts on plaque volume and coverage, whereas microglial activation remains fairly robust to perturbations of these functions. Thus, our work provides insights into the potential and limitations of targeting microglial activation as a pharmacological strategy for the treatment of AD.
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/drug therapy ; Microglia/metabolism ; Microglia/pathology ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Plaque, Amyloid
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13095
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration: Distribution, dose-response, and mechanisms of delivery

Kumar, Niyanta N / Jeffrey J. Lochhead / Michelle E. Pizzo / Geetika Nehra / Sam Boroumand / Gretchen Greene / Robert G. Thorne

Journal of controlled release. 2018 Sept. 28, v. 286

2018

Abstract: The intranasal route has been hypothesized to circumvent the blood-brain and blood-cerebrospinal fluid barriers, allowing entry into the brain via extracellular pathways along olfactory and trigeminal nerves and the perivascular spaces (PVS) of cerebral ... ...

Abstract	The intranasal route has been hypothesized to circumvent the blood-brain and blood-cerebrospinal fluid barriers, allowing entry into the brain via extracellular pathways along olfactory and trigeminal nerves and the perivascular spaces (PVS) of cerebral blood vessels. We investigated the potential of the intranasal route to non-invasively deliver antibodies to the brain 30 min following administration by characterizing distribution, dose-response, and mechanisms of antibody transport to and within the brain after administering non-targeted radiolabeled or fluorescently-labeled full length immunoglobulin G (IgG) to normal adult female rats. Intranasal [125I]-IgG consistently yielded highest concentrations in the olfactory bulbs, trigeminal nerves, and leptomeningeal blood vessels with their associated PVS. Intranasal delivery also resulted in significantly higher [125I]-IgG concentrations in the CNS than systemic (intra-arterial) delivery for doses producing similar endpoint blood concentrations. Importantly, CNS targeting significantly increased with increasing dose only with intranasal administration, yielding brain concentrations that ranged from the low-to-mid picomolar range with tracer dosing (50 μg) up to the low nanomolar range at higher doses (1 mg and 2.5 mg). Finally, intranasal pre-treatment with a previously identified nasal permeation enhancer, matrix metalloproteinase-9, significantly improved intranasal [125I]-IgG delivery to multiple brain regions and further allowed us to elucidate IgG transport pathways extending from the nasal epithelia into the brain using fluorescence microscopy. The results show that it may be feasible to achieve therapeutic levels of IgG in the CNS, particularly at higher intranasal doses, and clarify the likely cranial nerve and perivascular distribution pathways taken by antibodies to reach the brain from the nasal mucosae.
Keywords	adults ; antibodies ; blood ; blood vessels ; dose response ; females ; fluorescence microscopy ; gelatinase B ; immunoglobulin G ; intranasal administration ; iodine ; nasal mucosa ; nerve tissue ; olfactory bulb ; radiolabeling ; rats ; therapeutics
Language	English
Dates of publication	2018-0928
Size	p. 467-484.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2018.08.006
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration: Distribution, dose-response, and mechanisms of delivery.

Kumar, Niyanta N / Lochhead, Jeffrey J / Pizzo, Michelle E / Nehra, Geetika / Boroumand, Sam / Greene, Gretchen / Thorne, Robert G

Journal of controlled release : official journal of the Controlled Release Society

2018 Volume 286, Page(s) 467–484

Abstract	The intranasal route has been hypothesized to circumvent the blood-brain and blood-cerebrospinal fluid barriers, allowing entry into the brain via extracellular pathways along olfactory and trigeminal nerves and the perivascular spaces (PVS) of cerebral blood vessels. We investigated the potential of the intranasal route to non-invasively deliver antibodies to the brain 30 min following administration by characterizing distribution, dose-response, and mechanisms of antibody transport to and within the brain after administering non-targeted radiolabeled or fluorescently-labeled full length immunoglobulin G (IgG) to normal adult female rats. Intranasal [
MeSH term(s)	Administration, Intranasal ; Animals ; Brain/blood supply ; Brain/metabolism ; Female ; Immunoglobulin G/administration & dosage ; Immunoglobulin G/analysis ; Immunoglobulin G/blood ; Injections, Intra-Arterial ; Rats ; Rats, Sprague-Dawley ; Tissue Distribution ; Trigeminal Nerve/metabolism
Chemical Substances	Immunoglobulin G
Language	English
Publishing date	2018-08-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2018.08.006
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Article ; Online: Passive Immunotherapies for Central Nervous System Disorders: Current Delivery Challenges and New Approaches.

Kumar, Niyanta N / Pizzo, Michelle E / Nehra, Geetika / Wilken-Resman, Brynna / Boroumand, Sam / Thorne, Robert G

Bioconjugate chemistry

2018 Volume 29, Issue 12, Page(s) 3937–3966

Abstract: Passive immunotherapy, i.e., the administration of exogenous antibodies that recognize a specific target antigen, has gained significant momentum as a potential treatment strategy for several central nervous system (CNS) disorders, including Alzheimer's ... ...

Abstract	Passive immunotherapy, i.e., the administration of exogenous antibodies that recognize a specific target antigen, has gained significant momentum as a potential treatment strategy for several central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain cancer, among others. Advances in antibody engineering to create therapeutic antibody fragments or antibody conjugates have introduced new strategies that may also be applied to treat CNS disorders. However, drug delivery to the CNS for antibodies and other macromolecules has thus far proven challenging, due in large part to the blood-brain barrier and blood-cerebrospinal fluid barriers that greatly restrict transport of peripherally administered molecules from the systemic circulation into the CNS. Here, we summarize the various passive immunotherapy approaches under study for the treatment of CNS disorders, with a primary focus on disease-specific and target site-specific challenges to drug delivery and new, cutting edge methods.
MeSH term(s)	Central Nervous System Diseases/therapy ; Drug Delivery Systems/methods ; Humans ; Immunization, Passive/methods
Language	English
Publishing date	2018-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1024041-x
ISSN	1520-4812 ; 1043-1802
ISSN (online)	1520-4812
ISSN	1043-1802
DOI	10.1021/acs.bioconjchem.8b00548
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Article ; Online: Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution.

Cheloha, Ross W / Chen, Bingming / Kumar, Niyanta N / Watanabe, Tomoyuki / Thorne, Robert G / Li, Lingjun / Gardella, Thomas J / Gellman, Samuel H

Journal of medicinal chemistry

2017 Volume 60, Issue 21, Page(s) 8816–8833

Abstract: The parathyroid hormone receptor 1 (PTHR1) is a member of the B-family of GPCRs; these receptors are activated by long polypeptide hormones and constitute targets of drug development efforts. Parathyroid hormone (PTH, 84 residues) and PTH-related protein ...

Abstract	The parathyroid hormone receptor 1 (PTHR1) is a member of the B-family of GPCRs; these receptors are activated by long polypeptide hormones and constitute targets of drug development efforts. Parathyroid hormone (PTH, 84 residues) and PTH-related protein (PTHrP, 141 residues) are natural agonists of PTHR1, and an N-terminal fragment of PTH, PTH(1-34), is used clinically to treat osteoporosis. Conventional peptides in the 20-40-mer length range are rapidly degraded by proteases, which may limit their biomedical utility. We have used the PTHR1-ligand system to explore the impact of broadly distributed replacement of α-amino acid residues with β-amino acid residues on susceptibility to proteolysis and agonist activity. This effort led us to identify new PTHR1 agonists that contain α → β replacements throughout their sequences, manifest potent agonist activity in cellular assays, and display remarkable resistance to proteolysis, in cases remaining active after extended exposure to simulated gastric fluid. The strategy we have employed suggests a path toward identifying protease-resistant agonists of other B-family GPCRs.
MeSH term(s)	Amino Acids/chemistry ; Amino Acids/pharmacology ; Humans ; Ligands ; Parathyroid Hormone/pharmacology ; Parathyroid Hormone-Related Protein/pharmacology ; Protease Inhibitors/chemical synthesis ; Proteolysis/drug effects ; Receptor, Parathyroid Hormone, Type 1/agonists
Chemical Substances	Amino Acids ; Ligands ; PTH1R protein, human ; Parathyroid Hormone ; Parathyroid Hormone-Related Protein ; Protease Inhibitors ; Receptor, Parathyroid Hormone, Type 1
Language	English
Publishing date	2017-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.7b00876
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Article ; Online: Relative vascular permeability and vascularity across different regions of the rat nasal mucosa: implications for nasal physiology and drug delivery.

Kumar, Niyanta N / Gautam, Mohan / Lochhead, Jeffrey J / Wolak, Daniel J / Ithapu, Vamsi / Singh, Vikas / Thorne, Robert G

Scientific reports

2016 Volume 6, Page(s) 31732

Abstract: Intranasal administration provides a non-invasive drug delivery route that has been proposed to target macromolecules either to the brain via direct extracellular cranial nerve-associated pathways or to the periphery via absorption into the systemic ... ...

Abstract	Intranasal administration provides a non-invasive drug delivery route that has been proposed to target macromolecules either to the brain via direct extracellular cranial nerve-associated pathways or to the periphery via absorption into the systemic circulation. Delivering drugs to nasal regions that have lower vascular density and/or permeability may allow more drug to access the extracellular cranial nerve-associated pathways and therefore favor delivery to the brain. However, relative vascular permeabilities of the different nasal mucosal sites have not yet been reported. Here, we determined that the relative capillary permeability to hydrophilic macromolecule tracers is significantly greater in nasal respiratory regions than in olfactory regions. Mean capillary density in the nasal mucosa was also approximately 5-fold higher in nasal respiratory regions than in olfactory regions. Applying capillary pore theory and normalization to our permeability data yielded mean pore diameter estimates ranging from 13-17 nm for the nasal respiratory vasculature compared to <10 nm for the vasculature in olfactory regions. The results suggest lymphatic drainage for CNS immune responses may be favored in olfactory regions due to relatively lower clearance to the bloodstream. Lower blood clearance may also provide a reason to target the olfactory area for drug delivery to the brain.
Language	English
Publishing date	2016-08-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep31732
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery.

Pizzo, Michelle E / Wolak, Daniel J / Kumar, Niyanta N / Brunette, Eric / Brunnquell, Christina L / Hannocks, Melanie-Jane / Abbott, N Joan / Meyerand, M Elizabeth / Sorokin, Lydia / Stanimirovic, Danica B / Thorne, Robert G

The Journal of physiology

2017 Volume 596, Issue 3, Page(s) 445–475

Abstract: Key points: It is unclear precisely how macromolecules (e.g. endogenous proteins and exogenous immunotherapeutics) access brain tissue from the cerebrospinal fluid (CSF). We show that transport at the brain-CSF interface involves a balance between ... ...

Abstract	Key points: It is unclear precisely how macromolecules (e.g. endogenous proteins and exogenous immunotherapeutics) access brain tissue from the cerebrospinal fluid (CSF). We show that transport at the brain-CSF interface involves a balance between Fickian diffusion in the extracellular spaces at the brain surface and convective transport in perivascular spaces of cerebral blood vessels. Intrathecally-infused antibodies exhibited size-dependent access to the perivascular spaces and tunica media basement membranes of leptomeningeal arteries. Perivascular access and distribution of full-length IgG could be enhanced by intrathecal co-infusion of hyperosmolar mannitol. Pores or stomata present on CSF-facing leptomeningeal cells ensheathing blood vessels in the subarachnoid space may provide unique entry sites into the perivascular spaces from the CSF. These results illuminate new mechanisms likely to govern antibody trafficking at the brain-CSF interface with relevance for immune surveillance in the healthy brain and insights into the distribution of therapeutic antibodies. Abstract: The precise mechanisms governing the central distribution of macromolecules from the cerebrospinal fluid (CSF) to the brain and spinal cord remain poorly understood, despite their importance for physiological processes such as antibody trafficking for central immune surveillance, as well as several ongoing intrathecal clinical trials. In the present study, we clarify how IgG and smaller single-domain antibodies (sdAb) distribute throughout the whole brain in a size-dependent manner after intrathecal infusion in rats using ex vivo fluorescence and in vivo three-dimensional magnetic resonance imaging. Antibody distribution was characterized by diffusion at the brain surface and widespread distribution to deep brain regions along the perivascular spaces of all vessel types, with sdAb accessing a four- to seven-fold greater brain area than IgG. Perivascular transport involved blood vessels of all caliber and putative smooth muscle and astroglial basement membrane compartments. Perivascular access to smooth muscle basement membrane compartments also exhibited size-dependence. Electron microscopy was used to show stomata on leptomeningeal coverings of blood vessels in the subarachnoid space as potential access points allowing substances in the CSF to enter the perivascular space. Osmolyte co-infusion significantly enhanced perivascular access of the larger antibody from the CSF, with intrathecal 0.75 m mannitol increasing the number of perivascular profiles per slice area accessed by IgG by ∼50%. The results of the present study reveal potential distribution mechanisms for endogenous IgG, which is one of the most abundant proteins in the CSF, as well as provide new insights with respect to understanding and improving the drug delivery of macromolecules to the central nervous system via the intrathecal route.
MeSH term(s)	Animals ; Biological Transport ; Biological Transport, Active ; Blood-Brain Barrier/metabolism ; Brain/blood supply ; Brain/physiology ; Diffusion ; Drug Delivery Systems ; Extracellular Space/metabolism ; Female ; Immunoglobulin G/metabolism ; Injections, Spinal ; Optical Imaging ; Osmosis ; Rats ; Rats, Sprague-Dawley ; Single-Chain Antibodies/administration & dosage ; Single-Chain Antibodies/cerebrospinal fluid ; Single-Chain Antibodies/pharmacokinetics ; Tissue Distribution
Chemical Substances	Immunoglobulin G ; Single-Chain Antibodies
Language	English
Publishing date	2017-12-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP275105
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Microglial roles in Alzheimer's disease: An agent-based model to elucidate microglial spatiotemporal response to beta-amyloid.

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Article: Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration: Distribution, dose-response, and mechanisms of delivery

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Article ; Online: Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration: Distribution, dose-response, and mechanisms of delivery.

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Article ; Online: Passive Immunotherapies for Central Nervous System Disorders: Current Delivery Challenges and New Approaches.

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Article ; Online: Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution.

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Article ; Online: Relative vascular permeability and vascularity across different regions of the rat nasal mucosa: implications for nasal physiology and drug delivery.

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Article ; Online: Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery.

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