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Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation.
Acta Neuropathol Commun. 2013 Nov 13; 1:75.AN

Abstract

BACKGROUND

The Blood-brain barrier (BBB) controls brain supply with oxygen and nutrients, and protects the brain from toxic metabolites, such as beta-amyloid (Aβ) peptides. The neurovascular unit (NVU) couples vascular and neuronal functions by controlling BBB parameters based on brain needs. As such, NVU/BBB dysfunction, associated to irregularities in cerebral blood flow (CBF), has been proposed to contribute in the pathogenesis of Alzheimer's disease (AD), mainly by impairing cerebral Aβ clearance. However, the spatiotemporal contribution of the NVU/BBB in the neurodegenerative cascades remains elusive.

RESULTS

By using C57BL/6J mice subjected to right common carotid artery (rCCA) permanent ligation in order to induce mild chronic cerebral hypoperfusion, we show here that cerebral hypoperfusion induced NVU dysfunction by reducing ABCB1 protein expression in brain capillaries. ABCB1 reduction was mainly triggered by an enhanced Glycogen Synthase Kinase 3 (GSK3β) activation, which decreased β-catenin nuclear abundance. Moreover, cerebral hypoperfusion triggered early vascular deposition of peripherally applied human Aβ1-42 peptides, which has shifted from highly vascular to the parenchyma 6 weeks later, forming small stable Aβ deposits. Hypoperfusion induced a deregulation in glucose metabolism, as brain reperfusion, or the administration of a high dose of glucose, diminished GSK3β activation, recuperated β-catenin nuclear abundance, reestablished ABCB1 protein expression, and prevented Aβ vascular early deposition. These results demonstrate that mild chronic cerebral hypoperfusion creates a metabolically deregulated microenvironment, thus triggering the brain entry and aggregation of peripherally applied human Aβ1-42 peptides.

CONCLUSION

Our study offers new insights on the initiation of the neurodegenerative cascades observed in AD, which could be valuable in developing adequate treatment strategies.

Authors+Show Affiliations

No affiliation info availableNo affiliation info availableNo affiliation info availableNeuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier boul,, Québec City, QC G1V 4G2, Canada. serge.rivest@crchul.ulaval.ca.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24252187

Citation

ElAli, Ayman, et al. "Mild Chronic Cerebral Hypoperfusion Induces Neurovascular Dysfunction, Triggering Peripheral Beta-amyloid Brain Entry and Aggregation." Acta Neuropathologica Communications, vol. 1, 2013, p. 75.
ElAli A, Thériault P, Préfontaine P, et al. Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation. Acta Neuropathol Commun. 2013;1:75.
ElAli, A., Thériault, P., Préfontaine, P., & Rivest, S. (2013). Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation. Acta Neuropathologica Communications, 1, 75. https://doi.org/10.1186/2051-5960-1-75
ElAli A, et al. Mild Chronic Cerebral Hypoperfusion Induces Neurovascular Dysfunction, Triggering Peripheral Beta-amyloid Brain Entry and Aggregation. Acta Neuropathol Commun. 2013 Nov 13;1:75. PubMed PMID: 24252187.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation. AU - ElAli,Ayman, AU - Thériault,Peter, AU - Préfontaine,Paul, AU - Rivest,Serge, Y1 - 2013/11/13/ PY - 2013/11/06/received PY - 2013/11/06/accepted PY - 2013/11/21/entrez PY - 2013/11/21/pubmed PY - 2013/11/21/medline SP - 75 EP - 75 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 1 N2 - BACKGROUND: The Blood-brain barrier (BBB) controls brain supply with oxygen and nutrients, and protects the brain from toxic metabolites, such as beta-amyloid (Aβ) peptides. The neurovascular unit (NVU) couples vascular and neuronal functions by controlling BBB parameters based on brain needs. As such, NVU/BBB dysfunction, associated to irregularities in cerebral blood flow (CBF), has been proposed to contribute in the pathogenesis of Alzheimer's disease (AD), mainly by impairing cerebral Aβ clearance. However, the spatiotemporal contribution of the NVU/BBB in the neurodegenerative cascades remains elusive. RESULTS: By using C57BL/6J mice subjected to right common carotid artery (rCCA) permanent ligation in order to induce mild chronic cerebral hypoperfusion, we show here that cerebral hypoperfusion induced NVU dysfunction by reducing ABCB1 protein expression in brain capillaries. ABCB1 reduction was mainly triggered by an enhanced Glycogen Synthase Kinase 3 (GSK3β) activation, which decreased β-catenin nuclear abundance. Moreover, cerebral hypoperfusion triggered early vascular deposition of peripherally applied human Aβ1-42 peptides, which has shifted from highly vascular to the parenchyma 6 weeks later, forming small stable Aβ deposits. Hypoperfusion induced a deregulation in glucose metabolism, as brain reperfusion, or the administration of a high dose of glucose, diminished GSK3β activation, recuperated β-catenin nuclear abundance, reestablished ABCB1 protein expression, and prevented Aβ vascular early deposition. These results demonstrate that mild chronic cerebral hypoperfusion creates a metabolically deregulated microenvironment, thus triggering the brain entry and aggregation of peripherally applied human Aβ1-42 peptides. CONCLUSION: Our study offers new insights on the initiation of the neurodegenerative cascades observed in AD, which could be valuable in developing adequate treatment strategies. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/24252187/Mild_chronic_cerebral_hypoperfusion_induces_neurovascular_dysfunction_triggering_peripheral_beta_amyloid_brain_entry_and_aggregation_ L2 - https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-75 DB - PRIME DP - Unbound Medicine ER -