1. ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy
- Author
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Susanne M. A. van der Pol, Anna Carrano, Annemieke J.M. Rozemuller, Helga E. de Vries, Jack van Horssen, Jeroen J.M. Hoozemans, Gijs Kooij, Robert Veerhuis, Hripsime Snkhchyan, Pathology, Molecular cell biology and Immunology, Clinical chemistry, NCA - Neurobiology of mental health, and NCA - neurodegeneration
- Subjects
Male ,Aging ,medicine.medical_specialty ,Pathology ,Down-Regulation ,Gene Expression ,ATP-binding cassette transporter ,Blood–brain barrier ,Alzheimer Disease ,Internal medicine ,medicine ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,RNA, Messenger ,Cells, Cultured ,Aged ,P-glycoprotein ,Aged, 80 and over ,Messenger RNA ,Amyloid beta-Peptides ,Clusterin ,biology ,General Neuroscience ,Brain ,Endothelial Cells ,Transporter ,medicine.disease ,Peptide Fragments ,Capillaries ,Neoplasm Proteins ,Cerebral Amyloid Angiopathy ,Endocrinology ,medicine.anatomical_structure ,biology.protein ,Biomarker (medicine) ,ATP-Binding Cassette Transporters ,Female ,Neurology (clinical) ,Cerebral amyloid angiopathy ,Geriatrics and Gerontology ,Biomarkers ,Developmental Biology - Abstract
Alzheimer's disease (AD) is the most common form of dementia and marked by deposition of amyloid-β (Aβ) within the brain. Alterations of Aβ transporters at the neurovasculature may play a role in the disease process. We investigated the expression of ABC transporters P-glycoprotein (P-gp) and breast cancer related protein (BCRP) in non-neurologic controls, AD, and severe capillary cerebral amyloid angiopathy (capCAA) cases, which are characterized by deposition of Aβ within cerebral capillaries. Our data show that microvascular expression of P-gp and BCRP is strikingly decreased in capCAA-affected vessels but not in AD and control samples. Messenger RNA levels of P-gp, but not of BCRP, were downregulated in brain endothelial cells on exposure to oligomeric Aβ42, but not fibrillar Aβ42 or Aβ40. Coincubating Aβ42 together with clusterin, an amyloid-associated protein highly expressed in capCAA-affected vessels, strongly reduced levels of P-gp. In conclusion, accumulation of Aβ, in combination with clusterin, within and around cerebral capillaries, may further aggravate the disease process in AD by affecting P-gp expression. Loss of P-gp expression or activity may serve as a selective biomarker for ongoing capCAA.
- Published
- 2014
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