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

Halliday, Matthew R.; Rege, Sanket; Ma, Qingyi; Zhao, Zhen; Miller, Carol A.; Winkler, Ethan A.; Zloković, Berislav V.

doi:10.1038/jcbfm.2015.44

Cited by 501 publications

(523 citation statements)

References 42 publications

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“…The increase in vascular permeability in these mice was linked to a decrease in apoE-dependent pericyte-expressed LRP1 activation and a concomitant increase in CypA-MMP9 activity. In support of these findings, a human study using postmortem brain samples from control and AD subjects found accelerated pericyte degeneration in AD APOE-4 carriers compared with AD APOE-3 carriers and non-AD controls (126). Intriguingly, a significant increase in CypA and MMP-9 was also detected in pericytes and endothelial cells of APOE-4 subjects relative to APOE-3 subjects.…”

Section: Apoe and A Clearancementioning

confidence: 71%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

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In 1907, the German psychiatrist, Alois Alzheimer, published a case report, "On an unusual illness of the cerebral cortex," in which he described what we now know as Alzheimer's disease (AD) (1). More than a century after this landmark discovery, AD is now recognized as the most common cause of late-life dementia. AD pathology is characterized by the cerebral accumulation of amyloid plaques and neurofibrillary tangles, both of which consist predominantly of specific insoluble protein aggregates. The majority of AD cases are sporadic and have a relatively late onset, predominantly after the age of 65. This form of AD is known as late-onset AD (LOAD), in contrast to early-onset AD, which has a strong genetic component, is often autosomal dominant, and accounts for less than 1% of AD cases (2). While most genetic risk factors for LOAD identified in the past two decades have a relatively small impact on AD risk, extensive epidemiological, clinical, and pathological studies have established the APOE gene on chromosome 19 as the most important genetic risk factor for developing LOAD (3-5). This locus encodes a 299 amino acid glycoprotein (apoE) that is expressed in several cell types, with highest expression levels found in the liver and the brain, where it is expressed predominantly by astrocytes (6) and, to a lesser extent, microglia (7,8). The human APOE gene Abstract Alzheimer's disease (AD) is one of the fastestgrowing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid- (A). Here, we discuss the role of apoE on the biophysical properties and metabolism of the A peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including A) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond A, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.

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Section: Apoe and A Clearancementioning

confidence: 71%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

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“…35 In humans, cognitively healthy APOEε4 carriers showed higher age-dependent blood-brain barrier breakdown than APOEε3 carriers, 36 and whereas in patients with AD both APOEε4 and APOEε3 carriers had more pericyte degeneration than in healthy controls, the difference was most profound in the former. 37 In addition, in a large memory clinic cohort, amyloid deposition in those with small vessel disease was most aggravated in APOEε4 carriers. 30 Associations between vasoreactivity and dementia remained similar overall, and became stronger for APOEε4 carriers after adjustment for traditional cardiovascular risk factors.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia

Wolters

Bruijn

Hofman

et al. 2016

ATVB

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A bout 44 million people worldwide are living with dementia, and because of a rapidly aging population this number is predicted to nearly double every 20 years until 2050. 1,2 Consequently, the social and economic burden of dementia will increase enormously, unless preventive or curative measures can be established. Cardiovascular health is increasingly acknowledged as a key determinant in prevention of dementia, including Alzheimer disease (AD).3,4 Yet, the mechanism by which vascular damage leads to cognitive decline remains largely unknown.Although many studies have related cognitive function to static markers of cerebrovascular pathology, such as small vessel disease on magnetic resonance imaging and the retinal vasculature, few provide a functional measure of cerebral vascular disease. Cerebral vasoreactivity (CVR) reflects the ability of the cerebral arterioles and capillaries to dilate in response to increased neuronal metabolic demand, 5 and can be quantified in vivo using transcranial Doppler (TCD) or magnetic resonance imaging. Vasoreactivity is essential for maintenance of continuous cerebral perfusion, and impaired vasoreactivity is associated with (cardiovascular) mortality in the general population 6 and risk of stroke in the presence of flow-limiting carotid artery stenosis. 7 In addition, lower vasoreactivity correlates with higher volumes of cerebral white matter lesions, 8 which are strongly associated with cognitive decline and dementia.9 Several small cross-sectional studies have found CVR to be reduced in patients with dementia or mild cognitive impairment compared with healthy controls, 10-12 but its impact on cognitive decline and the risk of dementia is uncertain.We hypothesized that impaired CVR precedes dementia, and aimed to determine the association of CVR with cognitive decline and the risk of dementia in a population-based study.© 2015 American Heart Association, Inc. Materials and MethodsThis study is embedded within the Rotterdam study, an ongoing population-based cohort study in The Netherlands. TCD investigation with induction of hypercapnia was added to the core protocol for the second follow-up examination, from July 1997 to December 1999. Materials and Methods are available in the online-only Data Supplement. ResultsAmong 2569 eligible participants undergoing TCD with induced hypercapnia, no temporal bone window was present on either side in 632 (24.6%) individuals. Measurements could not be completed in 214 (8.3%) cases because of participants feeling anxious or unwell (n=54), lack of time (n=3), or other undocumented causes (n=157). In addition, in 94 participants we failed to obtain a reliable measurement of CVR despite adequate CO 2 induction, thus leaving a total of 1629 cases for analysis. Baseline characteristics of participants in comparison with nonparticipants are shown in Table 1. CVR was strongly impaired in current smokers and to a lesser extent in participants with a history of hypertension or diabetes mellitus. Conversely, higher systolic and diastoli...

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“…Our analysis replicates this phenomenon, as CT pathology was the driver of decreased cognitive performance following mTBI, with greater deleterious associations with consolidation and retrieval rather than encoding. This supports the idea that following ischemia and neuronal damage, the reduced antioxidant and biological activity of the ε 4 allele may exacerbate vascular endothelial injury (Bell et al., 2012; Halliday et al., 2016) and lead to cognitive deficits (Friedman et al., 1999). Similar results have been described in AD patients with left temporal and/or hippocampal damage, where a subtle decline in episodic memory occurs prior to the emergence of full dementia.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E epsilon 4 (APOE‐ε4) genotype is associated with decreased 6‐month verbal memory performance after mild traumatic brain injury

et al. 2017

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IntroductionThe apolipoprotein E (APOE) ε4 allele associates with memory impairment in neurodegenerative diseases. Its association with memory after mild traumatic brain injury (mTBI) is unclear.Methods mTBI patients (Glasgow Coma Scale score 13–15, no neurosurgical intervention, extracranial Abbreviated Injury Scale score ≤1) aged ≥18 years with APOE genotyping results were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK‐TBI Pilot) study. Cohorts determined by APOE‐ε4(+/−) were assessed for associations with 6‐month verbal memory, measured by California Verbal Learning Test, Second Edition (CVLT‐II) subscales: Immediate Recall Trials 1–5 (IRT), Short‐Delay Free Recall (SDFR), Short‐Delay Cued Recall (SDCR), Long‐Delay Free Recall (LDFR), and Long‐Delay Cued Recall (LDCR). Multivariable regression controlled for demographic factors, seizure history, loss of consciousness, posttraumatic amnesia, and acute intracranial pathology on computed tomography (CT).ResultsIn 114 mTBI patients (APOE‐ε4(−)=79; APOE‐ε4(+)=35), ApoE‐ε4(+) was associated with long‐delay verbal memory deficits (LDFR: B = −1.17 points, 95% CI [−2.33, −0.01], p = .049; LDCR: B = −1.58 [−2.63, −0.52], p = .004), and a marginal decrease on SDCR (B = −1.02 [−2.05, 0.00], p = .050). CT pathology was the strongest predictor of decreased verbal memory (IRT: B = −8.49, SDFR: B = −2.50, SDCR: B = −1.85, LDFR: B = −2.61, LDCR: B = −2.60; p < .001). Seizure history was associated with decreased short‐term memory (SDFR: B = −1.32, p = .037; SDCR: B = −1.44, p = .038).ConclusionThe APOE‐ε4 allele may confer an increased risk of impairment of 6‐month verbal memory for patients suffering mTBI, with implications for heightened surveillance and targeted therapies. Acute intracranial pathology remains the driver of decreased verbal memory performance at 6 months after mTBI.

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

Cited by 501 publications

References 42 publications

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Cerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia

Apolipoprotein E epsilon 4 (APOE‐ε4) genotype is associated with decreased 6‐month verbal memory performance after mild traumatic brain injury

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