Blood-Brain Barrier Breakdown in the Aging Human Hippocampus

Montagne, Axel; Barnes, Samuel; Sweeney, Melanie D.; Halliday, Matthew R.; Sagare, Abhay P.; Zhao, Zhen; Toga, Arthur W.; Jacobs, Russell E.; Liu, Collin Y.; Amezcua, Lilyana; Harrington, Michael G.; Chui, Helena C.; Law, Meng; Zloković, Berislav V.

doi:10.1016/j.neuron.2014.12.032

Cited by 1,549 publications

(1,706 citation statements)

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“…Future longitudinal imaging studies in the living human brain in APOE4 carriers and non-carriers are needed to address these important questions. Ideally, such studies should combine measurements of regional BBB integrity, particularly in the hippocampus, as recently reported, 37 with serial CSF biomarkers analyses of vascular/BBB and/or other cell-specific injury, and brain connectivity and structural changes, and neurophsychological testing. 38 Elevated CSF CypA and active MMP-9 levels, and an increase in albumin CSF/plasma ratio suggestive of BBB breakdown have been shown in living older cognitively normal APOE4/APOE3 carriers compared with the corresponding APOE3/APOE3 and APOE2/ APOE3 carriers with no cognitive impairment, 23 suggesting that APOE4 allele compared with APOE3 and/ or APOE2 leads to increased BBB permeability during cognitively normal aging.…”

Section: Discussionmentioning

confidence: 99%

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Halliday

Rege

et al. 2015

J Cereb Blood Flow Metab

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The blood-brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer's disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA-MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

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Section: Discussionmentioning

confidence: 99%

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Halliday

Rege

et al. 2015

J Cereb Blood Flow Metab

Self Cite

497

478

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“…Second, as CBF decreases, adherens and tight junctions in the blood–brain barrier are disrupted, resulting in increased diffusion of lipid‐soluble proteins across capillary walls. Subsequently, blood‐derived neurotoxic proteins accumulate in the brain resulting in suppressed capillary blood flow and neurodegeneration 38, 39. Such changes can be exacerbated in older adults as blood–brain barrier breakdown has been reported in the hippocampus with normal aging 38.…”

Section: Discussionmentioning

confidence: 99%

Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults

Kresge

Khan

Wagener

et al. 2018

JAHA

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BackgroundGlobal longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults.Methods and ResultsVanderbilt Memory and Aging Project participants who were free of clinical dementia, stroke, and heart failure (n=318, 73±7 years, 58% male) completed neuropsychological assessment and cardiac magnetic resonance to quantify GLS and LVEF. Linear regression models related GLS and LVEF to neuropsychological performances, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and APOE*ε4 status. Models were repeated with a cardiac×cognitive diagnosis interaction term. Compromised GLS (reflected by higher values) related to worse naming (β=−0.07, P=0.04), visuospatial immediate recall (β=−0.83, P=0.03), visuospatial delayed recall (β=−0.22, P=0.03), and verbal delayed recall (β=−0.11, P=0.007). LVEF did not relate to worse performance on any measure (P>0.18). No diagnostic interactions were observed.ConclusionsOur study results are among the first to suggest that compromised GLS relates to worse episodic memory and language performance among older adults who are free of clinical dementia, stroke, and heart failure. Subclinical cardiac dysfunction may correlate with cognitive health in late life, even when LVEF remains normal. The results add to growing evidence that GLS may be a more sensitive and preferred method for quantifying subclinical changes in cardiac function.

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“…Montagne et al . (2015) showed BBB disruption in the aging human hippocampus and cellular injury to pericytes. It cannot be ruled out that pericytes, astrocytes, or vascular smooth muscle cell dysfunction due to telomere shortening affects BBB integrity in this mouse model.…”

Section: Discussionmentioning

confidence: 99%

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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SummaryMicroglia are a proliferative population of resident brain macrophages that under physiological conditions self‐renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as ‘priming’. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first‐generation G1 mTerc−/−)‐ and late‐generation (third‐generation G3 and G4 mTerc−/−) telomerase‐deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late‐generation mTerc−/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc−/− microglia are comparable with microglia derived from G1 mTerc−/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc−/− microglia mice show an enhanced pro‐inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age‐associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood–brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

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Blood-Brain Barrier Breakdown in the Aging Human Hippocampus

Cited by 1,549 publications

References 50 publications

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

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