Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Luis O Soto-Rojas; B. Berenice Campa-Córdoba; Charles Harrington; Andrés Salas-Casas; Mario Hernandes-Alejandro; Ignacio Villanueva-Fierro; Marely Bravo-Muñoz; Linda Garcés-Ramírez; Fidel  De La Cruz-López; Miguel Angel Ontiveros-Torres; Goar  Gevorkian; Mar Pacheco-Herrero; José Luna-Muñoz

doi:10.3390/ijms22073654

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Luis O Soto-Rojas, B. Berenice Campa-Córdoba^* (Corresponding Author), Charles Harrington, Andrés Salas-Casas, Mario Hernandes-Alejandro, Ignacio Villanueva-Fierro, Marely Bravo-Muñoz, Linda Garcés-Ramírez, Fidel De La Cruz-López, Miguel Angel Ontiveros-Torres, Goar Gevorkian, Mar Pacheco-Herrero, José Luna-Muñoz

^*Corresponding author for this work

Instituto Politécnico Nacional

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immuno fluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.

Original language	English
Article number	3654
Number of pages	18
Journal	International Journal of Molecular Sciences
Volume	22
Issue number	7
DOIs	https://doi.org/10.3390/ijms22073654
Publication status	Published - 1 Apr 2021

Bibliographical note

Funding: This work was supported by Fondo Nacional de Ciencia y Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic (2015-3A2-127 to MP-H) and (2018-2019-2A3-208 to J.L.-M. and M.P.-H).
Acknowledgments: The authors want to express their gratitude to the following: P. Davies†(Albert Einstein College of Medicine, Bronx, NY, USA) and Lester I. Binder† (North Western, Chicago, IL,
USA) for the generous gift of mAbs TG-3 and Alz-50, and Tau-1, Tau-5, and Tau-7, respectively; Tec. Amparo Viramontes Pintos for the handling of the brain tissue; support in the confocal microscopy
unit of CIIDIR Durango, Instituto Politécnico Nacional; Union Medica University Clinic, Dominican
Republic, for their support and collaboration in the development of this research project. We also want to express our gratitude to the Mexican families who have donated the brain of their loved
ones affected by Alzheimer’s disease and made our research possible. This work is dedicated to the memory of José Raúl Mena López†
.
†Deceased.

Keywords

Alzheimer’s disease
fibrillar amyloid
pyroglutamate-modified amyloid-beta peptides
neurovascular unit
blood–brain barrier
caspase-5
Caspase-5
Neurovascular unit
Fibrillar amyloid
Pyroglutamate-modified amyloid-beta peptides
Blood–brain barrier

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Soto-Rojas, L. O., Campa-Córdoba, B. B., Harrington, C., Salas-Casas, A., Hernandes-Alejandro, M., Villanueva-Fierro, I., Bravo-Muñoz, M., Garcés-Ramírez, L., De La Cruz-López, F., Ontiveros-Torres, M. A., Gevorkian, G., Pacheco-Herrero, M., & Luna-Muñoz, J. (2021). Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains. International Journal of Molecular Sciences, 22(7), Article 3654. https://doi.org/10.3390/ijms22073654

Soto-Rojas, LO, Campa-Córdoba, BB, Harrington, C, Salas-Casas, A, Hernandes-Alejandro, M, Villanueva-Fierro, I, Bravo-Muñoz, M, Garcés-Ramírez, L, De La Cruz-López, F, Ontiveros-Torres, MA, Gevorkian, G, Pacheco-Herrero, M & Luna-Muñoz, J 2021, 'Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains', International Journal of Molecular Sciences, vol. 22, no. 7, 3654. https://doi.org/10.3390/ijms22073654

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title = "Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer{\textquoteright}s Disease Brains",

abstract = "Alzheimer{\textquoteright}s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immuno fluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.",

keywords = "Alzheimer{\textquoteright}s disease, fibrillar amyloid, pyroglutamate-modified amyloid-beta peptides, neurovascular unit, blood–brain barrier, caspase-5, Caspase-5, Neurovascular unit, Fibrillar amyloid, Pyroglutamate-modified amyloid-beta peptides, Blood–brain barrier",

author = "Soto-Rojas, {Luis O} and Campa-C{\'o}rdoba, {B. Berenice} and Charles Harrington and Andr{\'e}s Salas-Casas and Mario Hernandes-Alejandro and Ignacio Villanueva-Fierro and Marely Bravo-Mu{\~n}oz and Linda Garc{\'e}s-Ram{\'i}rez and {De La Cruz-L{\'o}pez}, Fidel and Ontiveros-Torres, {Miguel Angel} and Goar Gevorkian and Mar Pacheco-Herrero and Jos{\'e} Luna-Mu{\~n}oz",

note = "Funding: This work was supported by Fondo Nacional de Ciencia y Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic (2015-3A2-127 to MP-H) and (2018-2019-2A3-208 to J.L.-M. and M.P.-H). Acknowledgments: The authors want to express their gratitude to the following: P. Davies†(Albert Einstein College of Medicine, Bronx, NY, USA) and Lester I. Binder† (North Western, Chicago, IL, USA) for the generous gift of mAbs TG-3 and Alz-50, and Tau-1, Tau-5, and Tau-7, respectively; Tec. Amparo Viramontes Pintos for the handling of the brain tissue; support in the confocal microscopy unit of CIIDIR Durango, Instituto Polit{\'e}cnico Nacional; Union Medica University Clinic, Dominican Republic, for their support and collaboration in the development of this research project. We also want to express our gratitude to the Mexican families who have donated the brain of their loved ones affected by Alzheimer{\textquoteright}s disease and made our research possible. This work is dedicated to the memory of Jos{\'e} Ra{\'u}l Mena L{\'o}pez† . †Deceased. ",

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AU - Soto-Rojas, Luis O

AU - Campa-Córdoba, B. Berenice

AU - Harrington, Charles

AU - Salas-Casas, Andrés

AU - Hernandes-Alejandro, Mario

AU - Villanueva-Fierro, Ignacio

AU - Bravo-Muñoz, Marely

AU - Garcés-Ramírez, Linda

AU - De La Cruz-López, Fidel

AU - Ontiveros-Torres, Miguel Angel

AU - Gevorkian, Goar

AU - Pacheco-Herrero, Mar

AU - Luna-Muñoz, José

N1 - Funding: This work was supported by Fondo Nacional de Ciencia y Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic (2015-3A2-127 to MP-H) and (2018-2019-2A3-208 to J.L.-M. and M.P.-H). Acknowledgments: The authors want to express their gratitude to the following: P. Davies†(Albert Einstein College of Medicine, Bronx, NY, USA) and Lester I. Binder† (North Western, Chicago, IL, USA) for the generous gift of mAbs TG-3 and Alz-50, and Tau-1, Tau-5, and Tau-7, respectively; Tec. Amparo Viramontes Pintos for the handling of the brain tissue; support in the confocal microscopy unit of CIIDIR Durango, Instituto Politécnico Nacional; Union Medica University Clinic, Dominican Republic, for their support and collaboration in the development of this research project. We also want to express our gratitude to the Mexican families who have donated the brain of their loved ones affected by Alzheimer’s disease and made our research possible. This work is dedicated to the memory of José Raúl Mena López† . †Deceased.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immuno fluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.

AB - Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immuno fluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.

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KW - blood–brain barrier

KW - caspase-5

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KW - Neurovascular unit

KW - Fibrillar amyloid

KW - Pyroglutamate-modified amyloid-beta peptides

KW - Blood–brain barrier

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Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Abstract

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Keywords

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