Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers

It was recently suggested that beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) functions as an amyloid beta (A beta)-degrading enzyme; in addition to its better understood role as an APP secretase. Due to this finding we sought to understand the possible genetic risk contributed by the BACE2 locus to the development of late-onset Alzheimer's disease (AD). In this study, we report that common single nucleotide polymorphism (SNP) variation in BACE2 is associated with altered AD risk in apolipoprotein E gene (APOE) epsilon 4 variant (e4) non-carriers. In addition, in e4 non-carriers diagnosed with AD or mild cognitive impairment (MCI), SNPs within the BACE2 locus are associated with cerebrospinal fluid (CSF) levels of A beta 1-42. Further, SNP variants in BACE2 are also associated with BACE2 RNA expression levels suggesting a potential mechanism for the CSF A beta 1-42 findings. Lastly, overexpression of BACE2 in vitro resulted in decreased A beta 1-40 and A beta 1-42 fragments in a cell line model of A beta production. These findings suggest that genetic variation at the BACE2 locus modifies AD risk for those individuals who don't carry the e4 variant of APOE. Further, our data indicate that the biological mechanism associated with this altered risk is linked to amyloid generation or clearance possibly through BACE2 expression changes.National Institute on Aging (NIA); National Alzheimer's Coordinating Center (NACC) [U01 AG016976]; National Institute on Aging: Ruth Seemann, John Hopkins Alzheimer's Disease Research Center (NIA) [AG05146, P50 AG16570, AG05128]; NINDS [NS39764]; Glaxo Smith Kline [P50-AG053760, AG05144, P50AG05681, P50 AG05136, P30-AG13846, 211002]; Arizona Biomedical Research Commission [4001, 0011, 05_ 901]; Michael J. Fox Foundation [AG10161, HHSN-271-2013-00030C]; McGowan Endowment; Medical Research Council, local NHS trusts and Newcastle University; Medical Research Council; Safa Al-Sarraj; Netherlands Brain Bank; Stichting MS Research, Brain Net Europe; Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds; Internationale Stiching Alzheimer Onderzoek; NIH-NIA [R01-AG041232]; State of Arizona DHS (Arizona Alzheimer's Consortium) - NIH EUREKA [R01-AG034504]; NIH intramural funds; UK Dementia Research Institute; DRI Ltd - UK Medical Research Council; Alzheimer's Society; Alzheimer's Research UK - Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer'sAssociation; Alzheimer's Drug Discovery Foundation; Araclon Biotech; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd; Fujirebio; Johnson & Johnson Pharmaceutical Research & Development LLC.; Merck Co., Inc.; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Takeda Pharmaceutical Company; Canadian Institutes of Health Research isproviding funds; ADNI clinical sites in Canada; Foundation for the National Institutes of Health; Northern California Institute for Research and Education; Laboratory for Neuro Imaging at the University of Southern CaliforniaOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E epsilon 4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.Mueller Family Charitable Trust; Arizona Department of Health Services; National Institutes of Health [R01-AG041232, R01-AG049465-05]; Flinn FoundationOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence

Background: HIV-1 Clade C (Subtype C; HIV-1C) is responsible for greater than 50% of infections worldwide. Unlike clade B HIV-1 (Subtype B; HIV-1B), which is known to cause HIV associated dementia (HAD) in approximately 15% to 30% of the infected individuals, HIV-1C has been linked with lower prevalence of HAD (0 to 6%) in India and Ethiopia. However, recent studies report a higher prevalence of HAD in South Africa, Zambia and Botswana, where HIV-1C infections predominate. Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. HIV-1 Tat protein is a viral determinant of neurocognitive dysfunction. Therefore, we focused our study on the variations seen in tat gene and its contribution to HIV associated neuropathogenesis. Results: A phylogenetic analysis of tat sequences of Southern African (South Africa and Zambia) HIV isolates with those from the geographically distant Southeast Asian (India and Bangladesh) isolates revealed that Southern African tat sequences are distinct from Southeast Asian isolates. The proportion of HIV − 1C variants with an intact dicysteine motif in Tat protein (C30C31) was significantly higher in the Southern African countries compared to Southeast Asia and broadly paralleled the high incidence of HAD in these countries. Neuropathogenic potential of a Southern African HIV-1C isolate (from Zambia; HIV-1C1084i), a HIV-1C isolate (HIV-1IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1ADA) from the US were tested using in vitro assays to measure neurovirulence and a SCID mouse HIV encephalitis model to measure cognitive deficits. In vitro assays revealed that the Southern African isolate, HIV-1C1084i exhibited increased monocyte chemotaxis and greater neurotoxicity compared to Southeast Asian HIV-1C. In neurocognitive tests, SCID mice injected with MDM infected with Southern African HIV-1C1084i showed greater cognitive dysfunction similar to HIV-1B but much higher than those exposed to Southeast Asian HIV − 1C. Conclusions: We report here, for the first time, that HIV-1C from Southern African countries is genetically distinct from Southeast Asian HIV-1C and that it exhibits a high frequency of variants with dicysteine motif in a key neurotoxic HIV protein, Tat. Our results indicate that Tat dicysteine motif determines neurovirulence. If confirmed in population studies, it may be possible to predict neurocognitive outcomes of individuals infected with HIV-1C by genotyping Tat

Neuroscientists as Cartographers: Mapping the Crossroads of Gonadal Hormones, Memory and Age Using Animal Models

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Longitudinal Assessment of Intravoxel Incoherent Motion Diffusion-Weighted MRI Metrics in Cognitive Decline.

BACKGROUND: Advanced diffusion-based MRI biomarkers may provide insight into microstructural and perfusion changes associated with neurodegeneration and cognitive decline. PURPOSE: To assess longitudinal microstructural and perfusion changes using apparent diffusion coefficient (ADC) and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters in cognitively impaired (CI) and healthy control (HC) groups. STUDY TYPE: Prospective/longitudinal. POPULATION: Twelve CI patients (75% female) and 13 HC subjects (69% female). FIELD STRENGTH/SEQUENCE: 3 T; Spin-Echo-IVIM-DWI. ASSESSMENT: Two MRI scans were performed with a 12-month interval. ADC and IVIM-DWI metrics (diffusion coefficient [D] and perfusion fraction [f]) were generated from monoexponential and biexponential fits, respectively. Additionally, voxel-based correlations were evaluated between change in Montreal Cognitive Assessment (ΔMoCA) and baseline imaging parameters. STATISTICAL TESTS: Analysis of covariance with sex and age as covariates was performed for main effects of group and time (false discovery rate [FDR] corrected) with post hoc comparisons using Bonferroni correction. Partial-η RESULTS: Significant differences were found for the main effects of group (HC vs. CI) and time. For group effects, higher ADC, IVIM-D, and IVIM-f were observed in the CI group compared to HC (ADC: 1.23 ± 0.08 DATA CONCLUSION: These findings demonstrate that longitudinal differences between CI and HC cohorts can be measured using IVIM-based metrics. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2

A Component Of Premarinâ® Enhances Multiple Cognitive Functions And Influences Nicotinic Receptor Expression

In women, ovarian hormone loss at menopause has been related to cognitive decline, and some studies suggest that estrogen-containing hormone therapy (HT) can mitigate these effects. Recently, the Women\u27s Health Initiative study found that conjugated equine estrogens, the most commonly prescribed HT, do not benefit cognition. Isolated components of conjugated equine estrogens (tradename Premarin®) have been evaluated in vitro, with delta8,9-dehydroestrone (Δ8E1) and equilin showing the strongest neuroprotective profiles. It has not been evaluated whether Δ8E1 or equilin impact cognition or the cholinergic system, which is affected by other estrogens and known to modulate cognition. Here, in middle-aged, ovariectomized rats, we evaluated the effects of Δ8E1 and equilin treatments on a cognitive battery and cholinergic nicotinic receptors (nAChR). Specifically, we used 125I-labeled epibatidine binding to assay brain nicotinic receptor containing 4α and 2β subunits (α4β2-nAChR), since this nicotinic receptor subtype has been shown previously to be sensitive to other estrogens Δ8E1 enhanced spatial working, recent and reference memory Δ8E1 also decreased hippocampal and entorhinal cortex α4β2-nAChR expression, which was related to spatial reference memory performance. Equilin treatment did not affect spatial memory or rat α4β2-nAChR expression, and neither estrogen impacted 86Rb+ efflux, indicating lack of direct action on human α4β2 nAChR function. Both estrogens influenced vaginal smear profiles, uterine weights, and serum luteinizing hormone levels, analogous to classic estrogens. The findings indicate that specific isolated Premarin® components differ in their ability to affect cognition and nAChR expression. Taken with the works of others showing Δ8E1-induced benefits on several dimensions of health-related concerns associated with menopause, this body of research identifies Δ8E1 as a new avenue to be investigated as a potential component of HT that may benefit brain health and function during aging. © 2010 Elsevier Inc

ESHRD: deconvolution of brain homogenate RNA expression data to identify cell-type-specific alterations in Alzheimer's disease

We describe herein a bioinformatics approach that leverages gene expression data from brain homogenates to derive cell-type specific differential expression results. We found that differentially expressed (DE) cell-specific genes were mostly identified as neuronal, microglial, or endothelial in origin. However, a large proportion (75.7%) was not attributable to specific cells due to the heterogeneity in expression among brain cell types. Neuronal DE genes were consistently downregulated and associated with synaptic and neuronal processes as described previously in the field thereby validating this approach. We detected several DE genes related to angiogenesis (endothelial cells) and proteoglycans (oligodendrocytes). We present a cost- and time-effective method exploiting brain homogenate DE data to obtain insights about cell-specific expression. Using this approach we identify novel findings in AD in endothelial cells and oligodendrocytes that were previously not reported. We derived an enrichment score for each gene using a publicly available RNA profiling database generated from seven different cell types isolated from mouse cerebral cortex. We then classified the differential expression results from 3 publicly accessible Late-Onset Alzheimer's disease (AD) studies including seven different brain regions

Molecular biomarkers to track clinical improvement following an integrative treatment model in autistic toddlers

Objective: Identifying an objective, laboratory-based diagnostic tool (e.g., changes in gene expression), when used in conjunction with disease-specific clinical assessment, could increase the accuracy of the effectiveness of a therapeutic intervention. Methods: We assessed the association between treatment outcome and blood RNA expression before the therapeutic intervention to post-treatment (after one year) of five Autism Spectrum Disorder (ASD) toddlers who underwent an intensive cognitive-behavioral intervention integrated with psychomotor and speech therapy. Results: We found 113 significant Differentially Expressed genes (DEGs) enriched for the nervous system, immune system, and transcription and translation-related pathways. Some of these genes, as MALAT-1, TSPO, and CFL1, appear to be promising candidates. Conclusion: Our findings show that changes in peripheral gene expression could be used in conjunction with clinical scales to monitor a rehabilitation intervention's effectiveness in toddlers affected by ASD. These results need to be validated in a larger cohort

Leukocyte and cytokine variables in asymptomatic Pugs at genetic risk of necrotizing meningoencephalitis

BackgroundNecrotizing meningoencephalitis (NME, aka Pug dog encephalitis) is an inflammatory brain condition associated with advanced disease at initial presentation, rapid progression, and poor response to conventional immunomodulatory therapy.Hypothesis/objectivesThat genetic risk for NME, defined by a common germline DNA haplotype located on chromosome 12, is associated with altered blood cytokine concentrations and leukocyte subsets in asymptomatic Pugs.AnimalsForty Pug dogs asymptomatic for NME from a hospital sample.MethodsProspective observational cohort study, including germline genome-wide genotyping, plasma cytokine determination by multiplexed profiling, and leukocyte subset characterization by flow cytometric analysis.ResultsSeven (18%) dogs were high risk, 10 (25%) medium risk, and 23 (58%) low risk for NME, giving a risk haplotype frequency of 30%. High and medium risk Pugs had significantly lower proportion of CD4+ T cells (median 22% [range, 7.3%-38%] vs 29% [range, 16%-41%], P = .03) and higher plasma IL-10 concentrations than low-risk Pugs (median 14.11 pg/mL [range, 9.66-344.19 pg/mL] vs 12.21 pg/mL [range, 2.59-18.53 pg/mL], P = .001). No other variables were significantly associated with the NME haplotype-based risk.Conclusions and clinical importanceThese data suggest an immunological underpinning to NME and a biologic rationale for future clinical trials that investigate novel diagnostic, preventative, and therapeutic strategies for this disease