Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner

Johnson, Lance A.; Olsen, Reid H.J.; Merkens, Louise S.; DeBarber, Andrea E.; Steiner, Robert D.; Sullivan, Patrick M.; Maeda, Nobuyo; Raber, Jacob

doi:10.1016/j.nbd.2013.12.016

Cited by 75 publications

(61 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, to the best of our knowledge, this is the first demonstration of this effect within a cohort of PTSD patients. A longstanding question in the field of dementia is the relative contribution of apoE isoform vs apoE concentration in AD pathogenesis (Johnson et al, 2014), that is, whether it is the type or amount of apoE that is important. Could a similar query be of value in the context of PTSD?…”

Section: Discussionmentioning

confidence: 99%

“…Anxiety-Like Behavior, Nest Building, and Activity Monitoring Anxiety-like behavior was measured using the elevated zero maze as described (Johnson et al, 2014). Nest building was measured using an established protocol (Deacon, 2006), and activity was monitored using home-cage activity sensors (Biobserve, St Augustin, Germany).…”

Section: Chronic Variable Stressmentioning

confidence: 99%

“…Fear acquisition and extinction were analyzed using a Med Associates mouse fear conditioning system, and hippocampus-dependent spatial memory was tested using a modified version of the Morris water maze, similar to a previously described protocol (Johnson et al, 2014).…”

Section: Fear Memory and Extinction: Hippocampus-dependent Declarativmentioning

confidence: 99%

See 2 more Smart Citations

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Johnson

Zuloaga

Bidiman

et al. 2015

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Apolipoprotein E (apoE) is an essential component of lipoprotein particles in both the brain and periphery, and exists in three isoforms in the human population: E2, E3, and E4. ApoE has numerous, well-established roles in neurobiology. Most notably, E4 is associated with earlier onset and increased risk of Alzheimer's disease (AD). Although possession of E2 is protective in the context of AD, E2 appears to confer an increased incidence and severity of posttraumatic stress disorder (PTSD). However, the biological processes underlying this link remain unclear. In this study, we began to elucidate these associations by examining the effects of apoE on PTSD severity in combat veterans, and on PTSD-like behavior in mice with human apoE. In a group of 92 veterans with PTSD, we observed significantly higher Clinician-Administered PTSD Scale and PTSD Checklist scores in E2+ individuals, as well as alterations in salivary cortisol levels. Furthermore, we measured behavioral and biological outcomes in mice expressing human apoE after a single stressful event as well as following a period of chronic variable stress, a model of combat-related trauma. Mice with E2 showed impairments in fear extinction, and behavioral, cognitive, and neuroendocrine alterations following trauma. To the best of our knowledge, these data constitute the first translational demonstration of PTSD severity in men and PTSD-like symptoms in mice with E2, and point to apoE as a novel biomarker of susceptibility, and potential therapeutic target, for PTSD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Chronic Variable Stressmentioning

confidence: 99%

See 1 more Smart Citation

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Johnson

Zuloaga

Bidiman

et al. 2015

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Csf Plasma and Tissue Collectionmentioning

confidence: 99%

“…These observations suggest that the putative interactions between apoE and A ␤ may vary depending on the experimental conditions and pools of apoE and A ␤ that are studied. Additionally, brain-specifi c overexpression of the LDL receptor (LDLR), the major apoE receptor ( 25 ), leads to signifi cantly decreased brain apoE levels and signifi cantly reduced amyloid and A ␤ loads, presumably by accelerating apoE uptake ( 26,27 ).How apoE is involved in A ␤ metabolism is not completely understood, as net levels of apoE are only one part of the equation; the degree to which apoE is lipidated also significantly affects function. Lipidation of apoE in the CNS is performed by ABCA1 ( 28, 29 ), akin to the well-established role of ABCA1-mediated lipidation of apoA-I in the periphery ( 30 ).…”

mentioning

confidence: 99%

LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice

Stukas

Freeman

Lee

et al. 2014

Journal of Lipid Research

View full text Add to dashboard Cite

Journal of Lipid Research Volume 55, 20141721 of the apoE4 allele increases risk and decreases the age of onset of late-onset AD ( 2 ), the putative roles of apoE in AD pathogenesis have been a topic of intensive focus. apoE is the primary apolipoprotein secreted by astrocytes and microglia in the CNS, and lipidation of nascent apoEcontaining discoidal particles eventually leads to the formation of mature CNS HDL-like particles in cerebrospinal fl uid (CSF) ( 1, 3 ). It is well-established that amyloid burden in humans follows an isoform-dependent pattern of apoE4>apoE3>apoE2 ( 4-6 ). In contrast to human apoE, murine apoE exists in only one isoform with limited homology to human apoE. Amyloid burden is robust in AD mice expressing murine apoE and nearly abrogated in apoE-defi cient mice ( 7-11 ). Reconstitution of human apoE isoforms into AD mice greatly delays amyloid deposition relative to murine apoE, but retains the human isoform-specifi c infl uence on amyloid accumulation (12)(13)(14)(15)(16)(17). Taken together, the relative amyloid burden across murine and human apoE is: murine apoE>>apoE4>apoE3>apoE2>>apoE Ϫ / Ϫ . These observations clearly show that apoE affects amyloid burden in vivo. In vivo, neither apoE isoform nor gene dose significantly affects the rate of ␤ -amyloid (A ␤ ) production from amyloid precursor protein ( 16,17 ), leading to the consensus that apoE is largely involved in modulating the clearance of A ␤ peptides from the brain. apoE participates in each of the three known pathways of A ␤ clearance, including proteolytic degradation, egress across the blood-brain barrier, and interstitial fl uid drainage, although many details remain poorly understood ( 18,19 ). It is important to note, however, that apoE isoforms, levels, and lipidation status are all important variables.Abstract A key step in plasma HDL maturation from discoidal to spherical particles is the esterifi cation of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fl uid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating ␤ -amyloid (A ␤ ) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for A ␤ clearance is unknown. Here we characterized the impact of LCAT defi ciency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT defi ciency did not increase A ␤ or amyloid in APP/PS1 LCAT ؊ / ؊ mice. Finally, LCAT expression and plasma activity were unaffected by age or the ons...

show abstract