APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline

Autor: Giuseppe Barisano, Anne M. Fagan, Michael G. Harrington, Tammie L.S. Benzinger, Meng Law, Melanie D. Sweeney, Maricarmen Pachicano, Julia Tcw, John C. Morris, Peter S. Conti, Lon S. Schneider, Axel Montagne, Arthur W. Toga, Lina M. D'Orazio, Elizabeth Joe, Amy R. Nelson, Richard J. Caselli, John M. Ringman, Helena C. Chui, Berislav V. Zlokovic, Daniel A. Nation, Yining Chen, Ararat Chakhoyan, Abhay P. Sagare, David P. Buennagel, Eric M. Reiman, Judy Pa
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Apolipoprotein E
Aging
Apolipoprotein E4
Hippocampus
Neurodegenerative
Alzheimer's Disease
0302 clinical medicine
Cerebrospinal fluid
2.1 Biological and endogenous factors
Medicine
Aetiology
Cognitive decline
Alzheimer's Disease Related Dementias (ADRD)
Multidisciplinary
Temporal Lobe
Platelet-Derived Growth Factor beta
medicine.anatomical_structure
Matrix Metalloproteinase 9
Blood-Brain Barrier
Neurological
Parahippocampal Gyrus
Biomarker (medicine)
Female
lipids (amino acids
peptides
and proteins)
Cyclophilin A
Receptor
Heterozygote
General Science & Technology
tau Proteins
Blood–brain barrier
Article
Temporal lobe
03 medical and health sciences
Alzheimer Disease
mental disorders
Acquired Cognitive Impairment
Humans
Dementia
Cognitive Dysfunction
Alleles
Amyloid beta-Peptides
business.industry
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
medicine.disease
Brain Disorders
Capillaries
030104 developmental biology
Positron-Emission Tomography
Pericytes
business
Neuroscience
030217 neurology & neurosurgery
Zdroj: Nature
Nature, vol 581, iss 7806
ISSN: 1476-4687
0028-0836
Popis: Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
Databáze: OpenAIRE
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