Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma.

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

The association of apolipoprotein E (ApoE) genotype and cognitive outcomes in multiple sclerosis; a systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disorder commonly seen in young female adults. Cognitive impairment is one of the widespread symptoms of MS. In recent years multiple studies sought the possible risk factors for MS-related cognitive deficit. Apolipoprotein E (ApoE) genotype is one of the genetic factors which correlated significantly with cognitive status and it is a well-known risk factor for Alzheimer's Disease. In this systematic review and meta-analysis, we collected the current evidence to evaluate the association between the ApoE genotype and the cognitive outcomes in patients with MS. METHOD: Results of searches through Medline via PubMed, Scopus, and ISI web of science, as well as hand searching, were screened in the title/abstract and full-text stages. English observational studies in which the association between ApoE and cognitive outcomes, in patients with MS were included in this systematic review. Animal studies, conference abstracts, reviews, clinical trials, case reports, letters and withdrawn studies, were not included. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools and the meta-analysis was conducted with Comprehensive Meta-Analysis (CMA.2) software. The numbers of patients with impairment in both ApoE4+ and ApoE4- groups were utilized for the calculation of the odds ratios (ORs) with 95% confidence intervals (CI) and a 0.05 level of significance for p-value. RESULT: Out of 224 results of searching, 13 studies met the eligibility criteria and were included in our systematic review, and 5 of them were included in the quantitative synthesis. Eleven studies assessed the cognitive status of patients with MS in two groups of ApoE4+ and ApoE4- while 2 rests, reported the rate of ApoE4+ patients in cognitively impaired and non-impaired groups. The phenotype of MS was only Relapsing-remitting multiple sclerosis (RRMS) in 3 studies and in the other 10 studies, it was a mixture of RRMS, clinically isolated syndrome (CIS), and progressive MS. Most of the reports did not find a significant association between ApoE genotype and cognitive outcomes in patients with MS. Contrary to the expectations, patients in ApoE4- group were more likely to have impairment in Judgment of Line Orientation (JLO) (OR: 0.405; 95% CI: 0.173 to 0.949, p-value:0.038), while ApoE4+ patients had more rate of impairment in SRT (OR:1.901; 95%CI: 1.237 to 2.920; p-value:0.003). Appropriate identifying and dealing with cofounding factors were the most common source of bias in our included studies. CONCLUSION: ApoE may have a domain-specific association with cognitive impairment in MS patients. ApoE4 patients had more delayed responses to stimuli, but the rate of impaired visuospatial perception is lower in these patients. Based on the current evidence, there is a doubt about the clinical significance of this association.

A Time-to-Event Exposure-Response Model for Amyloid-Related Imaging Abnormalities Following Administration of Aducanumab to Subjects With Early Alzheimer Disease.

Amyloid-related imaging abnormalities with edema (ARIA-E) have been reported in patients with early Alzheimer disease treated with aducanumab. ARIA-E incidence has been observed to be dependent on both dose and apolipoprotein E4 carrier status. A time-to-event (TTE) approach applying data from 2 phase 3 studies (studies 301 and 302) was used to describe the effect of aducanumab serum exposure on the instantaneous risk of 2 end points: the first incidence of ARIA-E and time to ARIA-E resolution. A total of 3251 subjects with 826 events supported the TTE model to characterize the first ARIA-E event. The TTE resolution model was supported by data from 768 of 826 subjects who had ARIA-E resolved. Relationships between drug concentrations and ARIA-E events were modeled with a hazard function dependent on time, aducanumab serum concentrations, attenuation of aducanumab exposure effects with time (ie, potential for tolerance to aducanumab exposure), study, and apolipoprotein E4 carrier status. The TTE model showed that ARIA-E incidence rates were higher during the first 200 days, followed by a reduction in rates. The change in event rate reflects the attenuation of drug effect, thereby providing support for the current proposed titration regimen. Time to ARIA-E resolution was characterized by a constant baseline hazard with a probability to resolution affected by baseline ARIA-E severity and aducanumab concentration. ARIA-E resolution was found to be driven primarily by baseline hazard and time and suggested that aducanumab concentration effect is a minor contributor to the time to resolution of ARIA-E.

FTY720 decreases ceramides levels in the brain and prevents memory impairments in a mouse model of familial Alzheimer's disease expressing APOE4.

The protection mediated by the bioactive sphingolipid sphingosine-1-phosphate (S1P) declines during Alzheimer's disease (AD) progression, especially in patients carrying the apolipoprotein E ε4 (APOE4) isoform. The drug FTY720 mimics S1P bioactivity, but its efficacy in treating AD is unclear. Two doses of FTY720 (0.1 mg / kg and 0.5 mg / kg daily) were given by oral gavage for 15 weeks to transgenic mouse models of familial AD carrying human apolipoprotein E (APOE) APOE3 (E3FAD) or APOE4 (E4FAD). After 12 weeks of treatment, animals were subjected to behavioral tests for memory, locomotion, and anxiety. Blood was withdrawn at different time points and brains were collected for sphingolipids analysis by mass spectrometry, gene expression by RT-PCR and Aß quantification by ELISA. We discovered that low levels of S1P in the plasma is associated with a higher probability of failing the memory test and that FTY720 prevents memory impairments in E4FAD. The beneficial effect of FTY720 was induced by a shift of the sphingolipid metabolism in the brain towards a lower production of toxic metabolites, like ceramide d18:1/16:0 and d18:1/22:0, and reduction of amyloid-ß burden and inflammation. In conclusion, we provide further evidence of the druggability of the sphingolipid system in AD.

Vitamin C Supplementation, APOE4 Genotype and Cognitive Functioning in a Rural-Dwelling Cohort.

OBJECTIVE: Apolipoprotein E4 (APOE4) genotype has been implicated as a moderating factor in cognitive function studies. Although prior studies have suggested that vitamin C is associated with better cognitive function in elders, link between the two has been mixed. Limited data exist as to whether the APOE4 genotype influences these associations. Therefore, this study sought to determine whether the association between vitamin C and cognition in a rural community dwelling cohort differs by the APOE4 genotype. DESIGN AND PARTICIPANTS: Data were analyzed on 582 participants (n=183 men; n=399 women) from a rural community-based cohort. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status and The Executive Interview. APOE genotyping was ascertained by standard methods. The relation between vitamin C supplementation and cognition were analyzed first with ANOVA and then ANCOVA with age, gender, education as covariates. Analyses were initially run in the full sample and then split by APOE4 presence (yes/no). RESULTS: Overall, Vitamin C supplementation was associated with significantly better immediate memory (p=0.04), visuospatial skills (p=0.002), language (p=0.01), and global cognitive functioning (p=0.006). Among APOE4 non-carriers, vitamin C supplementation was positively associated with immediate memory (F[1,392] =6.7, p=0.01), visuospatial skills (F[1,391]=10.6, p=0.001), language (F[1,392]=13.0, p<0.001), attention (F[1,386]=7.9, p=0.005, and global cognition (F[1,382]=11.0, p=0.001. However, there was no significant link between vitamin C supplementation and cognition among APOE4 carriers. CONCLUSION: Vitamin C supplementation was found to be positively associated with cognition among this rural-dwelling community-based sample; however, the associations appeared to differ by APOE4 status. These data may suggest that targeted genotype-specific cognitive enhancement studies are needed to clarify the potential benefits of vitamin C supplementation.

Amyloid ß-interacting partners in Alzheimer's disease: From accomplices to possible therapeutic targets.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases in modern society because of insurmountable difficulties in early diagnosis and lack of therapeutic treatments. AD pathogenesis is tightly linked to the abnormal accumulation and aggregation of amyloid ß (Aß), seemingly the main causative factor of AD; however, intensive research on Aß has not yet explained the complexity of AD pathogenesis. Consequently, the role of other supportive partners of Aß have been elucidated and evaluated in the etiology of AD, and their potential molecular mechanisms have emerged as possible therapeutic targets. In this review, we compile information regarding Aß-interacting partners in normal conditions and AD pathology, and analyze their etiological roles in diverse areas. Furthermore, we integrate this information into suggestions for probable clinical applications for AD diagnosis and therapeutics. We include Aß-interacting partners localized to the cell surface and intracellular and extracellular compartments of different cell types ranging from the central nervous system to peripheral regions. Additionally, we expand the range of Aß-interacting partners by including not only proteins, but also inorganic substances like metals, expecting that one of these partners may yield a critical breakthrough in the field of AD diagnostics and therapeutic drug development.

Pharmacodynamic and pharmacokinetic analysis of apoE4 [L261A, W264A, F265A, L268A, V269A], a recombinant apolipoprotein E variant with improved biological properties.

Physiological levels of wild-type (wt) apolipoprotein E (apoE) in plasma mediate the clearance of cholesterol-rich atherogenic lipoprotein remnants while higher than normal plasma apoE concentrations fail to do so and trigger hypertriglyceridemia. This property of wt apoE reduces significantly its therapeutic value as a lead biological for the treatment of dyslipidemia. Recently, we reported the generation of a recombinant apoE variant, apoE4 [L261A, W264A, F265A, L268A, V269A] (apoE4mut1) with improved biological functions. Specifically, in apoE-deficient (apoE(-/-)) mice this variant can normalize high plasma cholesterol levels without triggering hypertriglyceridemia, even at supraphysiological levels of expression. In the present study we performed pharmacodynamic and pharmacokinetic analysis of apoE4mut1 in experimental mice. Using adenovirus-mediated gene transfer in LDL receptor deficient (LDLr(-/-)) mice, we show that the cholesterol lowering potential of apoE4mut1 is dependent on the expression of a functional classical LDLr. Bolus infusion of apoE4mut1-containing proteoliposomes in apoE(-/-) mice fed western-type diet for 6 weeks indicated that exogenously synthesized apoE4mut1 maintains intact its ability to normalize the high cholesterol levels of these mice with a maximum pharmacological effect obtained at 10h post-treatment. Interestingly, plasma cholesterol levels remained significantly reduced up to 24h following intravenous administration of apoE4mut1 proteoliposomes. Measurements of plasma apoE levels indicated that apoE4mut1 in the form of proteoliposomes used in the study has a half-life of 15.8h. Our data suggest that purified apoE4mut1 may be an attractive new candidate for the acute correction of hypercholesterolemia in subjects expressing functional LDL receptor.

Omega-3 fatty acids and risk of dementia: the Canadian Study of Health and Aging.

BACKGROUND: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) may protect against dementia, although epidemiologic studies have yielded inconclusive results. Fish is the main dietary source of n-3 PUFAs and is sometimes contaminated with mercury. This neurotoxicant may modify the association with dementia. OBJECTIVE: We evaluated the association of erythrocyte membrane total n-3 PUFAs, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and blood mercury with the incidence of dementia and Alzheimer disease (AD) in the Canadian Study of Health and Aging (CSHA) with adjustment for confounders including apolipoprotein E epsilon4 (APOE epsilon4) status. DESIGN: The CSHA is a cohort study of a representative sample of persons aged > or =65 y, conducted from 1991 to 2002. A subsample of 663 nondemented CSHA subjects with a complete clinical examination, blood samples, and follow-up information was eligible for prospective analyses on laboratory measurements. Of these, 149 were incident cases of dementia, including 105 with AD. RESULTS: In adjusted Cox regression models with age as the time scale, there were no associations between total n-3 PUFAs, DHA, or EPA and dementia or AD. In contrast, a mercury concentration in the highest quartile was associated with a reduced risk of dementia (hazard ratio: 0.53; 95% CI: 0.33, 0.88). However, significant risk reductions were limited to subjects with concentrations of both n-3 PUFAs and mercury that were above the median. There was no modification of risk by APOE epsilon4 status. CONCLUSIONS: No associations between n-3 PUFAs and dementia or AD were found. The results regarding mercury may indicate a spurious association.