Loss of Direct Vascular Contact to Astrocytes in the Hippocampus as an Initial Event in Alzheimer's Disease. Evidence from Patients, In Vivo and In Vitro Experimental Models.
Mol Neurobiol
; 61(8): 5142-5160, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38172288
ABSTRACT
Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus-a complex brain structure with a pivotal role in learning and memory-is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice-a model of AD-and to determine the impact of Aß40 and Aß42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood-brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aß40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aß42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer's disease.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Astrócitos
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Peptídeos beta-Amiloides
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Doença de Alzheimer
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Hipocampo
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Aged80
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Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Mol Neurobiol
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Argentina