Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease.
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ABSTRACT:
SUBMITTER: Panitch R
PROVIDER: S-EPMC8758485 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo investigate the association between APOE genotype and β-amyloid (Aβ) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer disease-related cognitive impairment (ADCI).MethodsThis was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aβ positivity, we performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach.ResultsIn comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aβ positivity (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.79), while in the SVCI group, ε2 carriers showed a higher frequency of Aβ positivity (OR 2.26, 95% CI 1.02-5.01). In particular, we observed an interaction effect of ε2 carrier status and diagnostic group on Aβ positivity (OR 5.12, 95% CI 1.93-13.56), in that relative to ε3 homozygotes, there were more Aβ-positive ε2 carriers in the SVCI group than in the ADCI group. We also identified latent subgroups of Aβ-positive APOE ε2 carriers with SVCI and Aβ-positive APOE ε4 carriers with ADCI.ConclusionsOur findings suggest that APOE ε2 is distinctly associated with Aβ deposition in patients with SVCI and those with ADCI. Our findings further suggest that there is a distinctive subgroup of Aβ-positive APOE ε2 carriers with SVCI among patients with cognitive impairment.
| S-EPMC7682916 | biostudies-literature
Project description:ObjectiveWe tested independent and interactive effects of Apolipoprotein E (ApoE) and pulse pressure (PP) concurrently and longitudinally across 9 years (3 waves) of episodic (EM) and semantic memory (SM) data from the Victoria Longitudinal Study.MethodWe assembled a sample of older adults (n = 570, baseline M age = 71, age range = 53-95) and used latent growth modeling to test 4 research goals.ResultsFirst, the best fitting memory model was 2 single latent variables for EM and SM, each exhibiting configural, metric, and partial scalar invariance. This model was analyzed as a parallel process model. Second, baseline level of PP predicted EM performance at centering age (75) and rate of 9-year EM change. Third, we observed no main effects of ApoE on EM or SM. Fourth, EM was affected by higher PP but differentially less so for carriers of the ApoE ε2 allele than the ε3 or ε4 alleles.ConclusionsPP is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across risk and protective allelic distribution of the ApoE gene.
| S-EPMC4420712 | biostudies-literature
Project description:Optical neuritis (ON), otherwise known as optical nerve damage, is a term used to describe various environmental and body conditions that lead to optic nerve dysfunction. Neurologists are well aware of conditions that cause optic neuropathy, such as trauma, infections, malnutrition, and various toxins. As optic neuritis is a multifactorial demyelinating or infectious process, genetic predisposition may also influence the progression of optic neuritis. This study aimed to evaluate the association of ON (with and without multiple sclerosis) with APOE alleles and APOE serum levels. We found that the APOE ε3/ε3 genotype was statistically less common in the ON group of males than in the control group (p = 0.045). Moreover, the APOE ε3/ε3 genotype had a 3.7-fold increase in the odds of ON development in males (OR = 3.698; CI: 1.503–9.095; p = 0.004). In contrast, the APOE ε3/ε4 genotype had a 4.1-fold decrease in the odds of ON development in males (OR = 0.242; CI: 0.083–0.704; p = 0.009). APOE serum levels were statistically significantly higher in the ON group than in the control group (p = 0.042). The APOE ε3/ε3 genotype may increase males’ risk of developing ON, while the ε3/ε4 genotype may reduce males’ risk of developing ON.
| S-EPMC9323366 | biostudies-literature
Project description:BackgroundCancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated.MethodsWe evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity.ResultsThere was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores.ConclusionsAPOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.
| S-EPMC7962698 | biostudies-literature
Project description:The blood-brain barrier (BBB) regulates the traffic of micromolecules and macromolecules between the peripheral blood and the central nervous system, to maintain brain homeostasis. BBB disruption and dysfunction accompany a variety of neurological disorders and are closely related with the neuroinflammatory cascades that are triggered by leukocyte infiltration and glial activation. Here, we explored the role of complement component 8 gamma (C8G) in the maintenance of BBB integrity. Previously, C8G was shown to inhibit neuroinflammation by interfering with the sphingosine-1-phosphate (S1P)-S1PR2 interaction. The results of the present study revealed that C8G is localized in perivascular astrocytes, whereas S1PR2 is expressed in endothelial cells (ECs). In the lipopolysaccharide (LPS)-induced neuroinflammation model, the intracerebroventricular administration of the recombinant C8G protein protected the integrity of the BBB, whereas shRNA-mediated C8G knockdown enhanced BBB permeability and neutrophil infiltration. Using pharmacological agonists and antagonists of S1PR2, we demonstrated that C8G inhibited the inflammatory activation of ECs in culture by antagonizing S1PR2. In the in vitro BBB model, the addition of the recombinant C8G protein preserved endothelial integrity, whereas the knockdown of C8G exacerbated endothelial leakage under inflammatory conditions. Together, our findings indicate an important role for astrocytic C8G in protecting the BBB in the inflamed brain, suggesting a novel mechanism of cross talk between astrocytes and ECs in terms of BBB maintenance.
| S-EPMC8209513 | biostudies-literature
Project description:We identified a rare coding variant (p.K420Q) in the complement component 7 (C7) gene affecting the risk of Alzheimer's disease. To investigate the cellular effects of the mutant, we performed RNA-seq in cell line overexpression wilt-type and mutant C7. U251 glioma cells with stable expression of mutant APP (K670N/M671L) (U251-APP cells), which produce Aβ42 under Dox inducing, were used as the model cell. Total RNA of U251-APP cells overexpressing wild type and mutant C7 proteins were subjected to transcriptome sequencing using Illumina Hiseq 4000 platform.
2018-11-22 | GSE101608 | GEO
Project description:ObjectivesMost studies of aging cognition have focused on risk factors for worse performance and on either genetic or environmental factors. In contrast, we examined whether 2 factors known to individually benefit aging cognition may interact to produce better cognition: environment-based positive age beliefs and the APOE ε2 gene.MethodThe sample consisted of 3,895 Health and Retirement Study participants who were 60 years or older at baseline and completed as many as 5 assessments of cognition over 8 years.ResultsAs predicted, positive age beliefs amplified the cognitive benefit of APOE ε2. In contrast, negative age beliefs suppressed the cognitive benefit of APOE ε2. We also found that positive age beliefs contributed nearly 15 times more than APOE ε2 to better cognition.DiscussionThis study provides the first known evidence that self-perceptions can influence the impact of a gene on cognition. The results underscore the importance of combined psychosocial and biological approaches to understanding cognitive function in older adults.
| S-EPMC7489069 | biostudies-literature
Project description:PurposeTo examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer's disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia.MethodsWe analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau.ResultsCompared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]: - 0.31 [- 0.45, - 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (βstd range: 0.27-0.51, all p < 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10 [- 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ.ConclusionOur data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.
| S-EPMC8175302 | biostudies-literature
Project description:Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.
| S-EPMC6136080 | biostudies-other
Project description:Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wlds allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wlds mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wlds mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/2J.Wlds mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.
| S-EPMC5441748 | biostudies-literature