The role of APOE in cerebrovascular dysfunction

Tai, Leon M.; Thomas, Riya; Marottoli, Felecia M.; Koster, Kevin P.; Kanekiyo, Takahisa; Morris, Alan; Bu, Guojun

doi:10.1007/s00401-016-1547-z

Cited by 166 publications

(152 citation statements)

References 146 publications

Supporting

Mentioning

151

Contrasting

Unclassified

Order By: Relevance

“…Previous studies show that apoE plays important roles in the function of blood-brain-barrier (BBB) (Bell et al, 2012; Fullerton et al, 2001; Hafezi-Moghadam et al, 2007; Tai et al, 2016). To test whether a lack of endogenous apoE further deteriorates the integrity of blood-spinal cord-barrier (BSCB) after injury, we detected the extravasation of IgG using immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Cheng

Zheng

et al. 2018

Experimental Neurology

View full text Add to dashboard Cite

Apolipoprotein E (apoE), a plasma lipoprotein well known for its important role in lipid and cholesterol metabolism, has also been implicated in many neurological diseases. In this study, we examined the effect of apoE on the pathophysiology of traumatic spinal cord injury (SCI). ApoE-deficient mutant (apoE−/−) and wild-type mice received a T9 moderate contusion SCI and were evaluated using histological and behavioral analyses after injury. At 3 days after injury, the permeability of spinal cord-blood-barrier, measured by extravasation of Evans blue dye, was significantly increased in apoE−/− mice compared to wild type. The inflammation and spared white matter was also significantly increased and decreased, respectively, in apoE−/− mice compared to the wild type ones. The apoptosis of both neurons and oligodendrocytes was also significantly increased in apoE−/− mice. At 42 days after injury, the inflammation was still robust in the injured spinal cord in apoE−/− but not wild type mice. CD45+ leukocytes from peripheral blood persisted in the injured spinal cord of apoE−/− mice. The spared white matter was significantly decreased in apoE−/− mice compared to wild type ones. Locomotor function was significantly decreased in apoE−/− mice compared to wild type ones from week 1 to week 8 after contusion. Treatment of exogenous apoE mimetic peptides partially restored the permeability of spinal cord-blood-barrier in apoE−/− mice after SCI. Importantly, the exogenous apoE peptides decreased inflammation, increased spared white matter and promoted locomotor recovery in apoE−/− mice after SCI. Our results indicate that endogenous apoE plays important roles in maintaining the spinal cord-blood-barrier and decreasing inflammation and spinal cord tissue loss after SCI, suggesting its important neuroprotective function after SCI. Our results further suggest that exogenous apoE mimetic peptides could be a novel and promising neuroprotective reagent for SCI.

show abstract

Section: Resultsmentioning

confidence: 99%

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Cheng

Zheng

et al. 2018

Experimental Neurology

View full text Add to dashboard Cite

show abstract

“…Alternatively, it is possible that individuals with preexisting sleep issues who have APOE ε4 are more susceptible to Aβ deposition in the brain, which in turns aggravates the sleep issues. In addition, the APOE ε4 allele is thought to disrupt cerebral blood flow 46 . Disruption of cerebral blood flow can affect brain protein synthesis and contribute to neuronal dysfunction in the brain 47 .…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Apolipoprotein ε4 Carrier Status and Sleep Characteristics in Cognitively Normal Older Adults

Kahya

Vidoni

Burns

et al. 2017

J Geriatr Psychiatry Neurol

View full text Add to dashboard Cite

The apolipoprotein (APOE) ε4 allele, a well-described genetic risk factor for late onset Alzheimer’s disease (AD), is associated with sleep disturbances even in cognitively normal older adults although it is not clear if this association is independent of sleep apnea. We sought to extend previous studies by examining if cognitively normal older adults without self-reported sleep apnea who carry the APOE ε4 allele have altered sleep characteristics compared to non-carriers. Data from n=36 [APOE ε4 carriers (n=9), non-carriers (n=27)] cognitively normal older adults [Clinical Dementia Rating Scale=0] without self-reported sleep apnea were used for these analyses. Participants wore an actigraph for 7 days to determine sleep characteristics. The Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale were used to assess sleep quality and daytime sleepiness, respectively. The APOE ε4 carriers had a higher number of awakenings compared to the non-carriers (p=0.02). There was no significant difference on the PSQI global score and the ESS; however, the PSQI subcomponent of daily disturbances was significantly higher in APOE ε4 carriers (p=0.03) indicating increased daytime dysfunction is related to disrupted sleep. This study provides evidence that individuals who are cognitively normal and genetically at risk for AD may have disrupted sleep. These findings are consistent with prior studies and suggest that sleep disruption may be present in the pre-symptomatic stages of AD.

show abstract

“…As APOE4 carriers also often respond differentially in clinical trials it is important to identify novel mechanistic processes underlying APOE4 -induced AD risk. Increasing evidence indicates that APOE modulates CV morphology and function (reviewed in [50]). In AD and AD-Tg models APOE4 is associated with CV dysfunction including basement membrane degradation and increased leakiness [50].…”

Section: Introductionmentioning

confidence: 99%

“…Increasing evidence indicates that APOE modulates CV morphology and function (reviewed in [50]). In AD and AD-Tg models APOE4 is associated with CV dysfunction including basement membrane degradation and increased leakiness [50]. Thus, incorporating human APOE4 in studies focused on the CV in AD is valuable.…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice

Thomas

Zuchowska

Morris

et al. 2016

acta neuropathol commun

Self Cite

104

View full text Add to dashboard Cite

Cerebrovascular (CV) dysfunction is emerging as a critical component of Alzheimer’s disease (AD), including altered CV coverage. Angiogenic growth factors (AGFs) are key for controlling CV coverage, especially during disease pathology. Therefore, evaluating the effects of AGFs in vivo can provide important information on the role of CV coverage in AD. We recently demonstrated that epidermal growth factor (EGF) prevents amyloid-beta (Aβ)-induced damage to brain endothelial cells in vitro. Here, our goal was to assess the protective effects of EGF on cognition, CV coverage and Aβ levels using an AD-Tg model that incorporates CV relevant AD risk factors. APOE4 is the greatest genetic risk factor for sporadic AD especially in women and is associated with CV dysfunction. EFAD mice express human APOE3 (E3FAD) or APOE4 (E4FAD), overproduce human Aβ42 and are a well characterized model of APOE pathology. Thus, initially the role of APOE and sex in cognitive and CV dysfunction was assessed in EFAD mice in order to identify a group for EGF treatment. At 8 months E4FAD female mice were cognitively impaired, had low CV coverage, high microbleeds and low plasma EGF levels. Therefore, E4FAD female mice were selected for an EGF prevention paradigm (300 μg/kg/wk, 6 to 8.5 months). EGF prevented cognitive decline and was associated with lower microbleeds and higher CV coverage, but not changes in Aβ levels. Collectively, these data suggest that EGF can prevent Aβ-induced damage to the CV. Developing therapeutic strategies based on AGFs may be particularly efficacious for APOE4-induced AD risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0387-3) contains supplementary material, which is available to authorized users.

show abstract

The role of APOE in cerebrovascular dysfunction

Cited by 166 publications

References 146 publications

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

The Relationship Between Apolipoprotein ε4 Carrier Status and Sleep Characteristics in Cognitively Normal Older Adults

Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice

Contact Info

Product

Resources

About