Molecular Mechanisms Underlying Amyloid Beta Peptide Mediated Upregulation of Vascular Cell Adhesion Molecule-1 in Alzheimer Disease.

Autor:	Salian VS; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)., Tang X; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)., Thompson KJ; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)., Curan GL; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)., Lowe VJ; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)., Li L; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)., Kalari KR; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.)., Kandimalla KK; Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (V.S.S., K.K.K.); Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota (G.L.C., V.J.L.); Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota (X.T., K.J.T., K.R.K.); and Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (L.L.) kkandima@umn.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Nov 19; Vol. 391 (3), pp. 430-440. Date of Electronic Publication: 2024 Nov 19.
DOI:	10.1124/jpet.124.002280
Abstrakt:	Amyloid β (A β ) deposition and neurofibrillary tangles are widely considered the primary pathological hallmarks of familial and sporadic forms of Alzheimer disease (AD). However, cerebrovascular inflammation, which is prevalent in 70% of AD patients, is emerging as another core feature of AD pathology. In our current work, we investigated the hypothesis that A β 42 exposure drives an increase in vascular cell adhesion molecule-1 (VCAM-1) expression, a cerebrovascular inflammatory marker expressed on the blood-brain barrier (BBB) endothelium in humans and murine models. We have demonstrated that the inflammation signaling pathway is upregulated in AD patient brains, and VCAM-1 expression is increased in AD patients compared with healthy controls. Furthermore, dynamic SPEC/CT imaging in APP,PS1 transgenic mice (a mouse model that overexpresses A β 42) demonstrated VCAM-1 upregulation at the BBB. Although there is a strong association between A β 42 exposure and an increase in VCAM-1 expression, the underlying mechanisms remain partially understood. Molecular mechanisms driving VCAM-1 expression at the BBB were investigated in polarized human cerebral microvascular endothelial cell monolayers. Moreover, by employing reverse-phase protein array assays and immunocytochemistry we demonstrated that A β 42 increases VCAM-1 expression via the Src/p38/MEK signaling pathway. Therefore, targeting the Src/p38/MEK pathway may help modulate VCAM-1 expression at the BBB and help mitigate cerebrovascular inflammation in Alzheimer disease. SIGNIFICANCE STATEMENT: Although considered a core pathological feature of Alzheimer disease, molecular pathways leading to cerebrovascular inflammation remain only partially understood. Moreover, clinical diagnostic methods for detecting cerebrovascular inflammation are underdeveloped. This study demonstrated the detection of VCAM-1 using radio-iodinated VCAM-1 antibody and single-photon emission computed tomography/computed tomography imaging. Additionally, exposure to A β 42 increases VCAM-1 expression on the blood-brain barrier endothelium via the Src/p38/MEK pathway. These findings are expected to aid in the development of diagnostic and therapeutic approaches for addressing cerebrovascular inflammation in AD. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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