Three major effects of APOEε4 on Aβ immunotherapy induced ARIA

The targeting of amyloid-beta (Aβ) plaques therapeutically as one of the primary causes of Alzheimer’s disease (AD) dementia has been an ongoing effort spanning decades. While some antibodies are extremely promising and have been moved out of clinical trials and into the clinic, most of these treatments show similar adverse effects in the form of cerebrovascular damage known as amyloid-related imaging abnormalities (ARIA). The two categories of ARIA are of major concern for patients, families, and prescribing physicians, with ARIA-E presenting as cerebral edema, and ARIA-H as cerebral hemorrhages (micro- and macro-). From preclinical and clinical trials, it has been observed that the greatest genetic risk factor for AD, APOEε4, is also a major risk factor for anti-Aβ immunotherapy-induced ARIA. APOEε4 carriers represent a large population of AD patients, and, therefore, limits the broad adoption of these therapies across the AD population. In this review we detail three hypothesized mechanisms by which APOEε4 influences ARIA risk: (1) reduced cerebrovascular integrity, (2) increased neuroinflammation and immune dysregulation, and (3) elevated levels of CAA. The effects of APOEε4 on ARIA risk is clear, however, the underlying mechanisms require more research

Transcriptional profiling predicts running promotes cerebrovascular remodeling in young but not midlife mice.

BACKGROUND: The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer\u27s disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood. RESULTS: To better understand the effects of exercise, we preformed transcriptional profiling on young (1-2 months) and midlife (12 months) C57BL/6 J (B6) male mice after 12 weeks of voluntary running. Data was compared to age-matched sedentary controls. Interestingly, the midlife running group naturally broke into two cohorts based on distance ran - either running a lot and more intensely (high runners) or running less and less intensely (low runners). Midlife high runners had lower LDL cholesterol as well as lower adiposity (%fat) compared to sedentary, than midlife low runners compared to sedentary suggesting more intense running lowered systemic markers of risk for age-related diseases including dementias. Differential gene analysis of transcriptional profiles generated from the cortex and hippocampus showed thousands of differentially expressed (DE) genes when comparing young runners to sedentary controls. However, only a few hundred genes were DE comparing either midlife high runners or midlife low runners to midlife sedentary controls. This indicates that, in our study, the effects of running are reduced through aging. Gene set enrichment analyses identified enrichment of genes involved in extracellular matrix (ECM), vascular remodeling and angiogenesis in young runners but not midlife runners. These genes are known to be expressed in multiple vascular-related cell types including astrocytes, endothelial cells, pericytes and smooth muscle cells. CONCLUSIONS: Taken together these results suggest running may best serve as a preventative measure to reduce risk for cerebrovascular decline. Ultimately, this work shows that exercise may be more effective to prevent dementia if introduced at younger ages

APOE ε4 and exercise interact in a sex-specific manner to modulate dementia risk factors

Abstract Introduction: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer\u27s disease and related dementias (ADRDs), affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and APOE ε4 affect similar processes in the body and brain. While both APOE ε4 and exercise have been studied extensively, their interactive effects are not well understood. Methods: To address this, male and female APOE ε3/ε3, APOE ε3/ε4, and APOE ε4/ε4 mice ran voluntarily from wean (1 month) to midlife (12 months). Longitudinal and cross-sectional phenotyping were performed on the periphery and the brain, assessing markers of risk for dementia such as weight, body composition, circulating cholesterol composition, murine daily activities, energy expenditure, and cortical and hippocampal transcriptional profiling. Results: Data revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum low-density lipoprotein concentration dependent on APOE genotype. Additionally, murine daily activities and energy expenditure were significantly influenced by an interaction between APOE genotype and running in both sexes. Transcriptional profiling of the cortex and hippocampus predicted that APOE genotype and running interact to affect numerous biological processes including vascular integrity, synaptic/neuronal health, cell motility, and mitochondrial metabolism, in a sex-specific manner. Discussion: These data in humanized mouse models provide compelling evidence that APOE genotype should be considered for population-based strategies that incorporate exercise to prevent ADRDs and other APOE-relevant diseases

A novel mouse model expressing human forms for complement receptors CR1 and CR2

Background The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. Results To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1long and CR1short) can be replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for either CR1long, CR1short or CR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1long, but not CR1short or CR1KO. Conclusion The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease

The APOEε3/ε4 Genotype Drives Distinct Gene Signatures in the Cortex of Young Mice

Introduction: Restrictions on existing APOE mouse models have impacted research toward understanding the strongest genetic risk factor contributing to Alzheimer\u27s disease (AD) and dementia, APOEε4 , by hindering observation of a key, common genotype in humans - APOEε3/ε4 . Human studies are typically underpowered to address APOEε4 allele risk as the APOEε4/ε4 genotype is rare, which leaves human and mouse research unsupported to evaluate the APOEε3/ε4 genotype on molecular and pathological risk for AD and dementia. Methods: As a part of MODEL-AD, we created and validated new versions of humanized APOEε3/ε3 and APOEε4/ε4 mouse strains that, due to unrestricted breeding, allow for the evaluation of the APOEε3/ε4 genotype. As biometric measures are often translatable between mouse and human, we profiled circulating lipid concentrations. We also performed transcriptional profiling of the cerebral cortex at 2 and 4 months (mos), comparing APOEε3/ε4 and APOEε4/ε4 to the reference APOEε3/ε3 using linear modeling and WGCNA. Further, APOE mice were exercised and compared to litter-matched sedentary controls, to evaluate the interaction between APOEε4 and exercise at a young age. Results: Expression of human APOE isoforms were confirmed in APOEε3/ε3, APOEε3/ε4 and APOEε4/ε4 mouse brains. At two mos, cholesterol composition was influenced by sex, but not APOE genotype. Results show that the APOEε3/ε4 and APOEε4/ε4 genotype exert differential effects on cortical gene expression. APOEε3/ε4 uniquely impacts \u27hormone regulation\u27 and \u27insulin signaling,\u27 terms absent in APOEε4/ε4 data. At four mos, cholesterol and triglyceride levels were affected by sex and activity, with only triglyceride levels influenced by APOE genotype. Linear modeling revealed APOEε3/ε4 , but not APOEε4/ε4 , affected \u27extracellular matrix\u27 and \u27blood coagulation\u27 related terms. We confirmed these results using WGCNA, indicating robust, yet subtle, transcriptional patterns. While there was little evidence of APOE genotype by exercise interaction on the cortical transcriptome at this young age, running was predicted to affect myelination and gliogenesis, independent of APOE genotype with few APOE genotype-specific affects identified. Discussion: APOEε4 allele dosage-specific effects were observed in circulating lipid levels and cortical transcriptional profiles. Future studies are needed to establish how these data may contribute to therapeutic development in APOEε3/ε4 and APOEε4/ε4 dementia patients

A novel mouse model expressing human forms for complement receptors CR1 and CR2.

BACKGROUND: The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer\u27s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. RESULTS: To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1 CONCLUSION: The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease

A Longitudinal Study of Families Created Using Egg Donation: Family Functioning at Age 5

Findings are reported from Phase 2 of a longitudinal study of family functioning in heterosexual-couple families with 5 year olds conceived using identity-release egg donation. Seventy-two egg donation families were compared to 50 in vitro fertilization (IVF) families (ethnicity: 93% White British) using standardized observational, interview, and questionnaire measures. There were no differences between family types in the quality of mother–child or father–child interaction, apart from lower structuring by fathers in egg donation families. Egg donation mothers and fathers reported higher levels of parenting stress and lower levels of confidence and competence than their IVF counterparts. Egg donation mothers reported lower social support and couple relationship quality, greater anger toward their child, and perceived their child as more angry and less happy, compared to IVF mothers. Egg donation fathers showed greater criticism and anger toward their child, less joy in parenting, and were less satisfied with the support they received, than IVF fathers. Children in egg donation families showed higher levels of externalizing problems than IVF children as rated by mothers, fathers, and teachers, whereas they were rated as having higher levels of internalizing problems by teachers only. Externalizing problems were predicted by mothers’ lower initial social support, steeper increases in parenting stress and greater concurrent criticism, whereas internalizing problems were associated with poorer initial couple relationship quality as rated by mothers. Both were predicted by fewer gains in reflective functioning. There was a moderation effect such that parenting stress was a stronger predictor of externalizing problems for egg donation than IVF families

Meox2 Haploinsufficiency Accelerates Axonal Degeneration in DBA/2J Glaucoma.

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma. Methods: Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a combination of genetic, biochemical, and immunofluorescence approaches. Results: URA identified Meox2 as a potential regulator of early gene expression changes in the optic nerve head (ONH) of DBA/2J mice. Meox2 haploinsufficiency did not affect the characteristic diseases of the iris or IOP elevation seen in DBA/2J mice but did cause a significant increase in the numbers of eyes with axon damage compared to controls. While young mice appeared normal, aged Meox2 haploinsufficient DBA/2J mice showed a 44% reduction in MEOX2 protein levels. This correlated with modulation of age- and disease-specific vascular and myeloid alterations. Conclusions: Our data support a model whereby Meox2 controls IOP-dependent vascular remodeling and neuroinflammation to promote axon survival. Promoting these earliest responses prior to IOP elevation may be a viable neuroprotective strategy to delay or prevent human glaucoma

The IKKâ related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists

The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogeneâ induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through siteâ specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGFâ receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i.e., TLR3; TLR4), revealing a stimulusâ selective role for TBK1 in mTORC1 regulation. By studying cultured macrophages and those isolated from genome edited mTOR S2159A knockâ in mice, we show that mTOR S2159 phosphorylation promotes mTORC1 signaling, IRF3 nuclear translocation, and IFNâ β production. These data demonstrate a direct mechanistic link between TBK1 and mTORC1 function as well as physiologic significance of the TBK1â mTORC1 axis in control of innate immune function. These data unveil TBK1 as a direct mTORC1 activator and suggest unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity, tumorigenesis, and disorders linked to chronic inflammation.SynopsisTBK1, an IKKâ related kinase that drives interferon production as well cancer cell proliferation and survival, phosphorylates mTOR to activate mTORC1 in response to EGF and innate immune agonists, suggesting unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity and tumorigenesis.TBK1 interacts with mTORC1 and phosphorylates mTOR on S2159 to increase its catalytic activity.Cells lacking TBK1 or expressing a mTOR S2159A allele exhibit reduced mTORC1 signaling in response to EGFâ receptor and TLR3/4 activation.Primary macrophages derived from genome edited mTOR S2159A mice exhibit reduced mTORC1 signaling in response to TLR3/4 activation.Primary macrophages treated with rapamycin as well as those derived from mTORS2159A mice produce reduced levels of IFNâ β due to impaired nuclear translocation of the transcription factor IRF3.Innate immune kinase TBK1â dependent activation of mTORC1 occurs in response to pathogen recognition and EGF receptor activation and drives interferon production, thus highlighting the role of mTOR for innate immunity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/1/embj201696164.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/2/embj201696164.reviewer_comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/3/embj201696164_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/4/embj201696164-sup-0001-EVFigs.pd

Three Hypervelocity White Dwarfs in Gaia DR2: Evidence for Dynamically Driven Double-Degenerate Double-Detonation Type Ia Supernovae

Double detonations in double white dwarf (WD) binaries undergoing unstable mass transfer have emerged in recent years as one of the most promising Type Ia supernova (SN Ia) progenitor scenarios. One potential outcome of this "dynamically driven double-degenerate double-detonation" (D^6) scenario is that the companion WD survives the explosion and is flung away with a velocity equal to its > 1000 km/s pre-SN orbital velocity. We perform a search for these hypervelocity runaway WDs using Gaia's second data release. In this paper, we discuss seven candidates followed up with ground-based instruments. Three sources are likely to be some of the fastest known stars in the Milky Way, with total Galactocentric velocities between 1000 and 3000 km/s, and are consistent with having previously been companion WDs in pre-SN Ia systems. However, although the radial velocity of one of the stars is > 1000 km/s, the radial velocities of the other two stars are puzzlingly consistent with 0. The combined five-parameter astrometric solutions from Gaia and radial velocities from follow-up spectra yield tentative 6D confirmation of the D^6 scenario. The past position of one of these stars places it within a faint, old SN remnant, further strengthening the interpretation of these candidates as hypervelocity runaways from binary systems that underwent SNe Ia.Comment: Accepted for publication in ApJ. Minor corrections for clarity. D6 spectra are available as ancillary data file