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Aguilar, Ximena
Publications (3 of 3) Show all publications
Zysk, M., Clausen, F., Aguilar, X., Sehlin, D., Syvänen, S. & Erlandsson, A. (2019). Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 72(1), 161-180
Open this publication in new window or tab >>Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 72, no 1, p. 161-180Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12- and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-beta (A beta) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced A beta pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, amyloid-beta, inflammation, Morris water maze, neurodegeneration astrocytes, PET, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-400408 (URN)10.3233/JAD-190572 (DOI)000500780700014 ()31561367 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationThe Swedish Brain Foundation
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Stenler, S., Roshanbin, S., Yilmaz Ugur, C., Rostami, J., Aguilar, X., Erlandsson, A., . . . Hultqvist, G. (2019). Over the BBB and into the cell: Pursuing intracellular targets for immunotherapy of Parkinson’s disease. In: : . Paper presented at 15th annual PEGS: The Essential Protein Engineering & Cell Therapy Summit, Boston, USA, April 8-12 2019.
Open this publication in new window or tab >>Over the BBB and into the cell: Pursuing intracellular targets for immunotherapy of Parkinson’s disease
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

The aim of our research is to modify therapeutic antibodies so that they can reach their dementia target inside cells located on the other side of the blood brain barrier. While the aggregates associated with Alzheimer’s are located extracellularly and thus readily available for antibodies that have crossed the BBB barrier, this is not the case for Parkinson’s disease. In this study, we focus on developing a peptide shuttle that can deliver antibodies not only over the BBB but also into neuronal cells where the Tau and a-synuclein aggregates can be found.

For this purpose, we have investigated the use of a peptide which binds to a receptor that co- localizes with the aggregates. Our in-house experience suggests that the peptide is not an efficient BBB transporter despite the fact that some groups have used it as such, but that it might be more suitable as a transporter for intracellular delivery.

We have successfully expressed recombinant antibodies with the peptide on the N-terminal of an antibody targeting the aggregates associated with Parkinson’s disease. Our initial studies indicate that the tyrosine on the N-terminal of the peptide needs to be free and unmodified to be able to enhance uptake into neuronal cells. This hinders the use of the normal labelling method which attaches radiolabelled iodine to tyrosines where the affinity for peptide target would be destroyed. We have been pursuing alternative methods, such as using click chemistry to attach the peptide which will leave the antibody free to be radiolabelled, as well as methods to detect unlabelled antibodies in vivo and in vitro.

We have assessed the peptide-assisted increase in uptake in appropriate neuronal cell line models. Furthermore, we have studied uptake and retention in brain in mouse models for Parkinson’s disease.

Keywords
Protein drug design, blood-brain-barrier, neurodegenerative diseases, immunotherapy, antibody-based drugs
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-401539 (URN)
Conference
15th annual PEGS: The Essential Protein Engineering & Cell Therapy Summit, Boston, USA, April 8-12 2019
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-22Bibliographically approved
Olsen, M., Aguilar, X., Sehlin, D., Fang, X. T., Antoni, G., Erlandsson, A. & Syvänen, S. (2018). Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease. Molecular Imaging and Biology, 20(4), 605-614
Open this publication in new window or tab >>Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease
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2018 (English)In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 20, no 4, p. 605-614Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (A beta) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[C-11]deprenyl ([C-11]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during A beta pathology progression. APP(ArcSwe) mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [C-11]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. A beta and GFAP levels were also measured with ELISA in brain homogenates. The intrabrain levels of aggregated A beta and reactive astrocytes were found to be elevated in APP(ArcSwe) compared with WT mice. GFAP and vimentin expression increased with age, i.e., with A beta pathology, in the APP(ArcSwe) mice. This was not the case for in vivo marker [C-11]DED that showed elevated binding of the same magnitude in APP(ArcSwe) mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. MAO-B levels are increased early in A beta pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant A beta plaque formation. Thus, [C-11]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of A beta pathology.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
PET, Amyloid-beta, Astrocytes, Astrogliosis, MAO-B, GFAP, Vimentin, [C-11]DED
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-361033 (URN)10.1007/s11307-017-1153-z (DOI)000438457800010 ()29297157 (PubMedID)
Funder
The Swedish Brain FoundationGun och Bertil Stohnes Stiftelse
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2018-09-21Bibliographically approved
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