TY - JOUR
T1 - Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains
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.
KW - Alzheimer’s disease
KW - fibrillar amyloid
KW - pyroglutamate-modified amyloid-beta peptides
KW - neurovascular unit
KW - blood–brain barrier
KW - caspase-5
KW - Caspase-5
KW - Neurovascular unit
KW - Fibrillar amyloid
KW - Pyroglutamate-modified amyloid-beta peptides
KW - Blood–brain barrier
UR - http://www.scopus.com/inward/record.url?scp=85103334888&partnerID=8YFLogxK
U2 - 10.3390/ijms22073654
DO - 10.3390/ijms22073654
M3 - Article
C2 - 33915754
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1422-0067
IS - 7
M1 - 3654
ER -