The role of apolipoprotein E in traumatic brain injury as determined by isoform and Abca1 haplodeficiency

Traumatic brain injury (TBI) is a significant public health concern as one of the leading causes of death and disability in the United States. TBI is due to the head forcibly contacting another object, or other mechanisms causing displacement of the brain within the skull. TBI is a complex multimodal disease process associated with high heterogeneity in outcomes, which suggests significant influence by genetic factors. Recent studies implicate the apolipoprotein E (APOE) gene in modulating TBI outcomes in an isoform-specific manner, specifically with inheritance of the APOE4 allele conferring worse outcome. The isoform-specific effect may be modulated by ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein that mediates the transport of lipids and cholesterol onto APOE, impacting its lipidation and stability. First, we examined whether there is an APOE isoform-specific response to TBI using mice expressing human APOE3+/+ or APOE4+/+ isoforms. At 3-months-old, TBI-treated mice received a craniotomy followed by a controlled cortical impact in the left hemisphere, whereas sham-treated mice received only a craniotomy. We found that both isoforms demonstrated similar cognitive impairments and transcriptional profiles following moderate TBI. We then examined the impact of ABCA1 deficiency on the response to traumatic brain injury using human APOE3+/+ and APOE4+/+ targeted replacement mice with only one functional copy of the Abca1 gene (E3/Abca1+/-; E4/Abca1+/-). We observed a common transcriptional response to TBI among the genotypes – E3/Abca1+/+, E4/Abca1+/+, E3/Abca1+/-, E4/Abca1+/- – however, E4/Abca1+/- had the highest proportion of unique transcripts. Additionally, we found that Abca1 haploinsufficiency increased the expression of microglia sensome genes among only APOE4 injured mice. Our results suggest that the APOE4 isoform is more susceptible to the consequences of Abca1 haplodeficiency. To identify modules, or interconnected gene clusters, correlated to TBI, APOE isoform, and Abca1 haplodeficiency, we performed Weighted Gene Co-expression Network Analysis (WGCNA). We determined that the module most correlated to TBI, regardless of APOE isoform or Abca1 deficiency, represented “immune response” with major hub genes including microglia-specific genes Trem2, Tyrobp, and Cd68. Unique modules were also associated with APOE isoform, and Abca1 haplodeficiency. Our results identify genes with a potential to become useful targets for future research

Advancing climate change health adaptation through implementation science

To date, there are few examples of implementation science studies that help guide climate-related health adaptation. Implementation science is the study of methods to promote the adoption and integration of evidence-based tools, interventions, and policies into practice to improve population health. These studies can provide the needed empirical evidence to prioritise and inform implementation of health adaptation efforts. This Personal View discusses five case studies that deployed disease early warning systems around the world. These cases studies illustrate challenges to deploying early warning systems and guide recommendations for implementation science approaches to enhance future research. We propose theory-informed approaches to understand multilevel barriers, design strategies to overcome those barriers, and analyse the ability of those strategies to advance the uptake and scale-up of climate-related health interventions. These findings build upon previous theoretical work by grounding implementation science recommendations and guidance in the context of real-world practice, as detailed in the case studies.Peer ReviewedArticle signat per 14 autors/es: Gila Neta, PhD; William Pan, DrPH; Prof Kristie Ebi, PhD; Daniel F Buss, PhD; Trisha Castranio, BS; Prof Rachel Lowe, PhD; Sadie J Ryan, PhD; Anna M Stewart-Ibarra, PhD; Limb K Hapairai, PhD; Meena Sehgal, MPH; Prof Michael C Wimberly, PhD; Leslie Rollock, DrPH; Prof Maureen Lichtveld, MD; John Balbus, MD"Postprint (published version

ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice

Producción CientíficaATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoproteins and regulates the generation of high density lipoproteins. Previously, we have shown that lack of Abca1 significantly increases amyloid deposition and cognitive deficits in Alzheimer’s disease model mice expressing human amyloid-β protein precursor (APP). The goal of this study was to determine if ABCA1 plays a role in memory deficits caused by amyloid-β (Aβ) oligomers and examine neurite architecture of pyramidal hippocampal neurons. Our results confirm previous findings that Abca1 deficiency significantly impairs spatial memory acquisition and retention in the Morris water maze and long-term memory in novel object recognition of APP transgenic mice at a stage of early amyloid pathology. Neither test demonstrated a significant difference between Abca1ko and wild-type (WT) mice. We also examined the effect of intra-hippocampal infused Aβ oligomers on cognitive performance of Abca1ko mice, compared to control infusion of scrambled Aβ peptide. Age-matched WT mice undergoing the same infusions were also used as controls. In this model system, we found a statistically significant difference between WT and Abca1ko mice infused with scrambled Aβ, suggesting that Abca1ko mice are vulnerable to the effect of mild stresses. Moreover, examination of neurite architecture in the hippocampi revealed a significant decrease in neurite length, number of neurite segments, and branches in Abca1ko mice when compared to WT mice. We conclude that mice lacking ABCA1 have basal cognitive deficits that prevent them from coping with additional stressors, which is in part due to impairment of neurite morphology in the hippocampus

Opposing effects ofApoe/Apoa1double deletion on amyloid-β pathology and cognitive performance in APP mice

Producción CientíficaATP binding cassette transporter A1 (encoded by ABCA1) regulates cholesterol efflux from cells to apolipoproteins A-I and E (ApoA-I and APOE; encoded by APOA1 and APOE, respectively) and the generation of high density lipoproteins. In Abca1 knockout mice (Abca1(ko)), high density lipoproteins and ApoA-I are virtually lacking, and total APOE and APOE-containing lipoproteins in brain substantially decreased. As the ε4 allele of APOE is the major genetic risk factor for late-onset Alzheimer's disease, ABCA1 role as a modifier of APOE lipidation is of significance for this disease. Reportedly, Abca1 deficiency in mice expressing human APP accelerates amyloid deposition and behaviour deficits. We used APP/PS1dE9 mice crossed to Apoe and Apoa1 knockout mice to generate Apoe/Apoa1 double-knockout mice. We hypothesized that Apoe/Apoa1 double-knockout mice would mimic the phenotype of APP/Abca1(ko) mice in regards to amyloid plaques and cognitive deficits. Amyloid pathology, peripheral lipoprotein metabolism, cognitive deficits and dendritic morphology of Apoe/Apoa1 double-knockout mice were compared to APP/Abca1(ko), APP/PS1dE9, and single Apoa1 and Apoe knockouts. Contrary to our prediction, the results demonstrate that double deletion of Apoe and Apoa1 ameliorated the amyloid pathology, including amyloid plaques and soluble amyloid. In double knockout mice we show that (125)I-amyloid-β microinjected into the central nervous system cleared at a rate twice faster compared to Abca1 knockout mice. We tested the effect of Apoe, Apoa1 or Abca1 deficiency on spreading of exogenous amyloid-β seeds injected into the brain of young pre-depositing APP mice. The results show that lack of Abca1 augments dissemination of exogenous amyloid significantly more than the lack of Apoe. In the periphery, Apoe/Apoa1 double-knockout mice exhibited substantial atherosclerosis and very high levels of low density lipoproteins compared to APP/PS1dE9 and APP/Abca1(ko). Plasma level of amyloid-β42 measured at several time points for each mouse was significantly higher in Apoe/Apoa1 double-knockout then in APP/Abca1(ko) mice. This result demonstrates that mice with the lowest level of plasma lipoproteins, APP/Abca1(ko), have the lowest level of peripheral amyloid-β. Unexpectedly, and independent of amyloid pathology, the deletion of both apolipoproteins worsened behaviour deficits of double knockout mice and their performance was undistinguishable from those of Abca1 knockout mice. Finally we observed that the dendritic complexity in the CA1 region of hippocampus but not in CA2 is significantly impaired by Apoe/Apoa1 double deletion as well as by lack of ABCA1. In conclusion: (i) plasma lipoproteins may affect amyloid-β clearance from the brain by the 'peripheral sink' mechanism; and (ii) deficiency of brain APOE-containing lipoproteins is of significance for dendritic complexity and cognition

Bmp2 and Bmp4 genetically interact to support multiple aspects of mouse development including functional heart development

Bone morphogenetic proteins (BMPs) have multiple roles during embryogenesis. Current data indicate that the dosage of BMPs is tightly regulated for normal development in mice. Since Bmp2 or Bmp4 homozygous mutant mice show early embryonic lethality, we generated compound heterozygous mice for Bmp2 and Bmp4 to explore the impact of lowered dosage of these BMP ligands. Genotyping pups bred between Bmp2 and Bmp4 heterozygous mice revealed that the ratio of adult compound heterozygous mice for Bmp2 and Bmp4 is much lower than expected. During embryogenesis, the compound heterozygous embryos showed several abnormalities, including defects in eye formation, body wall closure defects, and ventricular septal defects (VSD) in the heart. However, the ratio of the compound heterozygous embryos was the same as expected. Caesarean sections at E18.5 revealed that half of the compound heterozygotes died soon after birth, and the majority of the dead individuals exhibited VSD. Survivors were able to grow to adults, but their body weight was significantly lower than control littermates. They demonstrated progressive abnormalities in the heart, eventually showing a branched leaflet in atrioventricular valves. These results suggest that the dosage of both BMP2 and 4 is critical for functional heart formation during embryogenesis and after birth. genesis 47:374–384, 2009. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63084/1/20511_ftp.pd

Mice Lacking Alkbh1 Display Sex-Ratio Distortion and Unilateral Eye Defects

Escherichia coli AlkB is a 2-oxoglutarate- and iron-dependent dioxygenase that reverses alkylated DNA damage by oxidative demethylation. Mouse AlkB homolog 1 (Alkbh1) is one of eight members of the newly discovered family of mammalian dioxygenases.In the present study we show non-Mendelian inheritance of the Alkbh1 targeted allele in mice. Both Alkbh1(-/-) and heterozygous Alkbh1(+/-) offspring are born at a greatly reduced frequency. Additionally, the sex-ratio is considerably skewed against female offspring, with one female born for every three to four males. Most mechanisms that cause segregation distortion, act in the male gametes and affect male fertility. The skewing of the sexes appears to be of paternal origin, and might be set in the pachythene stage of meiosis during spermatogenesis, in which Alkbh1 is upregulated more than 10-fold. In testes, apoptotic spermatids were revealed in 5-10% of the tubules in Alkbh1(-/-) adults. The deficiency of Alkbh1 also causes misexpression of Bmp2, 4 and 7 at E11.5 during embryonic development. This is consistent with the incompletely penetrant phenotypes observed, particularly recurrent unilateral eye defects and craniofacial malformations.Genetic and phenotypic assessment suggests that Alkbh1 mediates gene regulation in spermatogenesis, and that Alkbh1 is essential for normal sex-ratio distribution and embryonic development in mice

ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms

Abstract Expression of human Apolipoprotein E (APOE) modulates the inflammatory response in an isoform specific manner, with APOE4 isoform eliciting a stronger pro-inflammatory response, suggesting a possible mechanism for worse outcome following traumatic brain injury (TBI). APOE lipidation and stability is modulated by ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein that transports lipids and cholesterol onto APOE. We examined the impact of Abca1 deficiency and APOE isoform expression on the response to TBI using 3-months-old, human APOE3 +/+ (E3/Abca1 +/+) and APOE4 +/+ (E4/Abca1 +/+ ) targeted replacement mice, and APOE3 +/+ and APOE4 +/+ mice with only one functional copy of the Abca1 gene (E3/Abca1 +/− ; E4/Abca1 +/−). TBI-treated mice received a craniotomy followed by a controlled cortical impact (CCI) brain injury in the left hemisphere; sham-treated mice received the same surgical procedure without the impact. We performed RNA-seq using samples from cortices and hippocampi followed by genome-wide differential gene expression analysis. We found that TBI significantly impacted unique transcripts within each group, however, the proportion of unique transcripts was highest in E4/Abca1 +/− mice. Additionally, we found that Abca1 haplodeficiency increased the expression of microglia sensome genes among only APOE4 injured mice, a response not seen in injured APOE3 mice, nor in either group of sham-treated mice. To identify gene networks, or modules, correlated to TBI, APOE isoform and Abca1 haplodeficiency, we used weighted gene co-expression network analysis (WGCNA). The module that positively correlated to TBI groups was associated with immune response and featured hub genes that were microglia-specific, including Trem2, Tyrobp, Cd68 and Hexb. The modules positively correlated with APOE4 isoform and negatively to Abca1 haplodeficient mice represented “protein translation” and “oxidation-reduction process”, respectively. Our results reveal E4/Abca1 +/− TBI mice have a distinct response to injury, and unique gene networks are associated with APOE isoform, Abca1 insufficiency and injury