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• W3081987135 abstract "•Dlgap2 QTL associates with working memory decline in Diversity Outbred (DO) mice•DLGAP2 variants associate with AD by GWAS in human populations•DLGAP2 gene and protein expression are associated with cognitive decline in humans•Results highlight translational relevance of DO mice for studying complex traits Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer’s dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates. Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer’s dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates. Aging is the leading risk factor for a number of disorders, including dementias such as Alzheimer’s disease. The mechanisms that underlie healthy aging—particularly, the cognitive aspects—remain poorly understood. Research suggests that genetics play a significant role in determining an individual’s susceptibility or resilience to cognitive decline and dementia (Harris and Deary, 2011Harris S.E. Deary I.J. The genetics of cognitive ability and cognitive ageing in healthy older people.Trends Cogn. Sci. 2011; 15: 388-394Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar; Ridge et al., 2013Ridge P.G. Mukherjee S. Crane P.K. Kauwe J.S. Alzheimer’s Disease Genetics ConsortiumAlzheimer’s disease: analyzing the missing heritability.PLoS ONE. 2013; 8: e79771Crossref PubMed Scopus (160) Google Scholar). Identification of precise genetic factors involved would provide insight into mechanisms underlying increased susceptibility and uncover therapeutic targets. The mouse represents a critical resource to identify genetic factors influencing complex traits due to well-defined genetic backgrounds, well-controlled environmental conditions, and lower sample size requirements for genetic mapping than human populations. Recent efforts to expand the genetic resources available in the mouse have resulted in the development of the Diversity Outbred (DO) panel (Churchill et al., 2012Churchill G.A. Gatti D.M. Munger S.C. Svenson K.L. The Diversity Outbred mouse population.Mamm. Genome. 2012; 23: 713-718Crossref PubMed Scopus (205) Google Scholar; Logan et al., 2013Logan R.W. Robledo R.F. Recla J.M. Philip V.M. Bubier J.A. Jay J.J. Harwood C. Wilcox T. Gatti D.M. Bult C.J. et al.High-precision genetic mapping of behavioral traits in the diversity outbred mouse population.Genes Brain Behav. 2013; 12: 424-437Crossref PubMed Scopus (72) Google Scholar), which is derived from an 8-parent population segregating approximately 40 million variants (Srivastava et al., 2017Srivastava A. Morgan A.P. Najarian M.L. Sarsani V.K. Sigmon J.S. Shorter J.R. Kashfeen A. McMullan R.C. Williams L.H. Giusti-Rodríguez P. et al.Genomes of the Mouse Collaborative Cross.Genetics. 2017; 206: 537-556Crossref PubMed Scopus (84) Google Scholar). The resulting offspring provide precision and power for genetic analysis of complex traits such as cognitive decline in aging. Here, we perform a large-scale, cross-sectional evaluation of cognitive performance in the DO population aged 6 to 18 months and identify a single protein-coding positional candidate (disk-associated large protein 2, Dlgap2) likely mediating observed age-related decline. Across a subset of DO mice, we find that morphologic variation among dendritic spine populations significantly correlates with cognitive outcomes. As Dlgap2 is a critical component of spines (Jiang-Xie et al., 2014Jiang-Xie L.F. Liao H.M. Chen C.H. Chen Y.T. Ho S.Y. Lu D.H. Lee L.J. Liou H.H. Fu W.M. Gau S.S. Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits.Mol. Autism. 2014; 5: 32Crossref PubMed Scopus (45) Google Scholar), this finding provides an avenue for future mechanistic investigation into the observed association between Dlgap2 and cognitive decline. Finally, we demonstrate that Dlgap2 is associated with cognitive decline and Alzheimer’s dementia (AD) in diverse human populations. Results highlight the utility of the mouse to (1) inform studies in human patients and (2) enable prioritization of genes and variants for further study. To identify genes involved in regulating the maintenance of cognitive function during aging, working memory was evaluated on the T-maze (Wenk, 2001Wenk G.L. Assessment of spatial memory using the T maze.Curr. Protoc. Neurosci. 2001; (Chapter 8: Unit 8.5B)PubMed Google Scholar) at 6, 12, or 18 months in 487 DO mice (Figure 1A). Working memory declined with age, F(2, 484) = 2.8, p = 0.03, one-tailed (Figure 1B). No effect of sex was observed on working memory performance, F(1, 484) = 0.02, p = 0.90. To identify genetic factors regulating working memory, we next performed genetic mapping. A quantitative trait locus (QTL) on chromosome 8 (chr8) (Figure 1C) that interacted with age to mediate working memory performance across the lifespan (LOD = 12.5, 1.5 LOD interval = 14.3–14.6 Mb, p < 0.05) was identified. Allelic coefficient plots demonstrate that, at 6 months of age, the non-obese diabetic (NOD) background contributes a lower working memory score, while the 129 and B6 backgrounds contribute higher working memory scores (Figure 1D, top). Age interactions with this locus were largely driven by NOD, B6, and 129 at 12 months of age (Figure 1D, top; Figures S1A and S1B). We also see age interactions across the QTL haplotype region (Figure S1C). A single protein-coding gene, Dlgap2, is located within the QTL interval (Figure 1D, bottom), highlighting Dlgap2 as the most likely positional candidate mediating working memory decline as a function of aging. SNP association tests within the QTL region using the most up-to-date Sanger sequencing information identified one high-confidence SNP and a single structural variant that differed between NOD and 129 within the intronic regions of the Dlgap2 gene (Figure S1D). Dlgap2 is a critical component of the postsynaptic density involved in regulating synaptic function and dendritic spine morphology (Li et al., 2017Li J. Zhang W. Yang H. Howrigan D.P. Wilkinson B. Souaiaia T. Evgrafov O.V. Genovese G. Clementel V.A. Tudor J.C. et al.Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders.Nat. Neurosci. 2017; 20: 1150-1161Crossref PubMed Scopus (45) Google Scholar). Given studies linking structural alterations in dendritic spine morphology with age-related changes in cognitive function (Dickstein et al., 2013Dickstein D.L. Weaver C.M. Luebke J.I. Hof P.R. Dendritic spine changes associated with normal aging.Neuroscience. 2013; 251: 21-32Crossref PubMed Scopus (126) Google Scholar; Dumitriu et al., 2010Dumitriu D. Hao J. Hara Y. Kaufmann J. Janssen W.G. Lou W. Rapp P.R. Morrison J.H. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment.J. Neurosci. 2010; 30: 7507-7515Crossref PubMed Scopus (259) Google Scholar; Boros et al., 2019Boros B.D. Greathouse K.M. Gearing M. Herskowitz J.H. Dendritic spine remodeling accompanies Alzheimer’s disease pathology and genetic susceptibility in cognitively normal aging.Neurobiol. Aging. 2019; 73: 92-103Crossref PubMed Scopus (24) Google Scholar), we measured the number and functional subtypes of spines in the hippocampus in a subset of DO mice at 6, 12, or 18 months of age (Figure 1E). We observed no changes in total spine density or distribution of spine type (thin, stubby, or mushroom; Table S1) with age. Neither spine density nor spine type correlated with cognitive outcomes at 6 or 12 months of age (Figure S2). However, by 18 months, there was a significant correlation between both the percentage of thin and stubby spines and working memory performance (Figures 1F–1H), suggesting that maintenance of high numbers of thin spines combined with lower numbers of stubby spines is beneficial for maintaining cognitive function during aging (Dumitriu et al., 2010Dumitriu D. Hao J. Hara Y. Kaufmann J. Janssen W.G. Lou W. Rapp P.R. Morrison J.H. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment.J. Neurosci. 2010; 30: 7507-7515Crossref PubMed Scopus (259) Google Scholar). We next sought to test the translational relevance of this finding by evaluating the association of DLGAP2 with clinically diagnosed dementia in human populations. We evaluated SNPs within the DLGAP2 region (±50 kb) within published and pending genome-wide association studies (GWASs) of clinical Alzheimer’s disease. Among individuals with European ancestry (Jansen et al., 2019Jansen I.E. Savage J.E. Watanabe K. Bryois J. Williams D.M. Steinberg S. Sealock J. Karlsson I.K. Hägg S. Athanasiu L. et al.Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk.Nat. Genet. 2019; 51: 404-413Crossref PubMed Scopus (435) Google Scholar), one locus just downstream of DLGAP2 was associated with AD: top SNP, rs2957061; p = 3.6 × 10−5; β = −0.02; odds ratio (OR) = 0.98; Figure S3A, Table S2). Among African American individuals, a locus within DLGAP2 was associated with AD: top SNP, chr8:1316870; minor allele frequency (MAF) = 0.01; p = 9.2 × 10−5; β = −0.86, OR = 0.42; Figures 2A and S3B; Table S3). A previous GWAS (White et al., 2017White C.C. Yang H.S. Yu L. Chibnik L.B. Dawe R.J. Yang J. Klein H.U. Felsky D. Ramos-Miguel A. Arfanakis K. et al.Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.PLoS Med. 2017; 14: e1002287Crossref PubMed Scopus (42) Google Scholar) reported that rs34130287C, a SNP within the first intron of DLGAP2, was suggestively associated with worse residual cognition (p = 4.0 × 10−6), a trait that quantified the gap between observed and predicted cognitive performance after regressing out the effect of neuropathology. DLGAP2 was not pursued as a potential candidate because NCBI and Ensembl annotations, at the time of the prior report, did not include rs34130287C within DLGAP2. However, as of February 2019, current annotations place this SNP within DLGAP2. Using the same dataset and methods as initially reported (White et al., 2017White C.C. Yang H.S. Yu L. Chibnik L.B. Dawe R.J. Yang J. Klein H.U. Felsky D. Ramos-Miguel A. Arfanakis K. et al.Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.PLoS Med. 2017; 14: e1002287Crossref PubMed Scopus (42) Google Scholar), we observed a significant relationship between the overall methylation pattern of the DLGAP2 region in the dorsolateral prefrontal cortex (DLPFC) and residual cognition (p = 0.038; Figure S3C). As methylation at the DLGAP2 locus has been shown to influence Dlgap2 expression in mouse (Chertkow-Deutsher et al., 2010Chertkow-Deutsher Y. Cohen H. Klein E. Ben-Shachar D. DNA methylation in vulnerability to post-traumatic stress in rats: evidence for the role of the post-synaptic density protein Dlgap2.Int. J. Neuropsychopharmacol. 2010; 13: 347-359Crossref PubMed Scopus (54) Google Scholar), we hypothesize that the effect of this locus on cognitive function is mediated by alterations in Dlgap2 expression in the DLPFC. We next sought to test this hypothesis by evaluating the association of DLGAP2 with cognitive function and dementia in human populations. Across the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP), lower levels of DLGAP2 mRNA in the DLPFC of post-mortem human brain tissue were associated with poorer cognitive performance at the final visit prior to death (β = 0.10, p = 0.01) and faster cognitive decline over all study visits (β = 0.01, p = 0.002; Figure 2B). This relationship was strongest among individuals with clinically diagnosed AD (Figure 2C). When assessing protein levels of DLGAP2 measured with tandem mass tag mass spectrometry (Johnson et al., 2020Johnson E.C.B. Dammer E.B. Duong D.M. Ping L. Zhou M. Yin L. Higginbotham L.A. Guajardo A. White B. Troncoso J.C. et al.Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation.Nat. Med. 2020; 26: 769-780Crossref PubMed Scopus (116) Google Scholar), we observed a consistent finding with lower levels of DLGAP2 protein associated with a faster rate of cognitive decline (β = 0.29, p < 0.001; Figure S3D). To assess differences in DLGAP2 expression during various stages of cognitive impairment, we evaluated DLPFC mRNA expression of DLGAP2 across ROS/MAP. Those with mild cognitive impairment (MCI) and clinically diagnosed AD had lower levels of expression compared to patients with normal cognition, F(2, 528) = 4.4, p = 0.01 (Figure 2D). A similar decrease of DLGAP2 was observed in two independent datasets covering 5 brain regions (Table S4), strengthening our confidence in these findings. As DLGAP2 is a component of synapses (Li et al., 2017Li J. Zhang W. Yang H. Howrigan D.P. Wilkinson B. Souaiaia T. Evgrafov O.V. Genovese G. Clementel V.A. Tudor J.C. et al.Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders.Nat. Neurosci. 2017; 20: 1150-1161Crossref PubMed Scopus (45) Google Scholar) and highly correlated with expression of the neuronal marker ENO2 (Figure 2E, left), it is possible that this decrease of DLGAP2 is due to neurodegeneration that occurs in MCI and Alzheimer’s disease. However, when considering only neuronal expression data from laser-capture microdissected neurons (Liang et al., 2008Liang W.S. Reiman E.M. Valla J. Dunckley T. Beach T.G. Grover A. Niedzielko T.L. Schneider L.E. Mastroeni D. Caselli R. et al.Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons.Proc. Natl. Acad. Sci. USA. 2008; 105: 4441-4446Crossref PubMed Scopus (374) Google Scholar) to control for number of neurons evaluated, a significant decrease in DLGAP2 remained (Figure 2E, right). This suggests that reduced DLGAP2 occurs independent of frank neurodegeneration. While not associated with neurodegeneration, we next evaluated whether DLGAP2 was associated with other neuropathological hallmarks of Alzheimer’s disease measured with immunohistochemistry (IHC). Lower levels of DLGAP2 were associated with greater β-amyloid load in the DLPFC (β = −0.13, p = 0.002). Similarly, lower levels of DLGAP2 were associated with more neurofibrillary tangles in the DLPFC (β = −0.11, p = 0.02). No associations were observed with non-Alzheimer neuropathologies (Table S5; p values > 0.10). Despite the recent increase in availability and accessibility of genomic technologies, our understanding of the genetic mechanisms underlying complex traits remains poor. This is due, in part, to the difficulty in assigning causality to GWAS hits, a number of which occur in non-coding regions of the genome (Zhang and Lupski, 2015Zhang F. Lupski J.R. Non-coding genetic variants in human disease.Hum. Mol. Genet. 2015; 24: R102-R110Crossref PubMed Scopus (215) Google Scholar). For example, the two loci highlighted here (Figures 2A and S3A) fall within complex genomic regions, making the biological mechanism driving the observed associations difficult to interpret. However, by combining these results with studies performed in the mouse, we not only identify Dlgap2 as a potential causal gene in the region but also highlight structural plasticity and modification of spine type (Figures 1E–1H) as a mechanism putatively involved in modifying cognitive decline. An additional factor complicating the identification of disease-causative genes using GWAS is a lack of statistical power, particularly in under-represented populations where sample size is relatively limited (Popejoy and Fullerton, 2016Popejoy A.B. Fullerton S.M. Genomics is failing on diversity.Nature. 2016; 538: 161-164Crossref PubMed Scopus (529) Google Scholar). As a result, population-specific genetic mechanisms underlying diseases, and treatments that may prevent or cure them, remain undiscovered. To better inform population-specific analyses, mouse studies offer a powerful way to prioritize candidates. In particular, the DO population provides an advantage over previous genetically diverse resources, including a higher degree of genetic diversity and smaller haplotype blocks, leading to more precise genomic mapping (Churchill et al., 2012Churchill G.A. Gatti D.M. Munger S.C. Svenson K.L. The Diversity Outbred mouse population.Mamm. Genome. 2012; 23: 713-718Crossref PubMed Scopus (205) Google Scholar). A caveat to this increased genetic diversity is the large number of allelic combinations present at any given locus. Although the present study was not sufficiently powered to estimate all heterozygous allelic combinations driving the effects, we were still able to identify founder effects in an eight-state additive model. By doing so, our mapping strategy nominated only one protein coding gene with well-known functions in regulating synaptic throughput, structure, and function (Jiang-Xie et al., 2014Jiang-Xie L.F. Liao H.M. Chen C.H. Chen Y.T. Ho S.Y. Lu D.H. Lee L.J. Liou H.H. Fu W.M. Gau S.S. Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits.Mol. Autism. 2014; 5: 32Crossref PubMed Scopus (45) Google Scholar; Chertkow-Deutsher et al., 2010Chertkow-Deutsher Y. Cohen H. Klein E. Ben-Shachar D. DNA methylation in vulnerability to post-traumatic stress in rats: evidence for the role of the post-synaptic density protein Dlgap2.Int. J. Neuropsychopharmacol. 2010; 13: 347-359Crossref PubMed Scopus (54) Google Scholar), highlighting the importance of this biological pathway to working memory. Although it is possible that these variants play a role in distal gene regulation, other sources of evidence supported our decision to move forward with DLGAP2 as a top candidate for tests in human cohorts. This was based on combining our interactive mapping result highlighting Dlgap2, biological priors (Jiang-Xie et al., 2014Jiang-Xie L.F. Liao H.M. Chen C.H. Chen Y.T. Ho S.Y. Lu D.H. Lee L.J. Liou H.H. Fu W.M. Gau S.S. Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits.Mol. Autism. 2014; 5: 32Crossref PubMed Scopus (45) Google Scholar), and our finding that variation in spine type is correlated with memory outcomes in aging DO mice that is consistent with findings in human studies (Boros et al., 2017Boros B.D. Greathouse K.M. Gentry E.G. Curtis K.A. Birchall E.L. Gearing M. Herskowitz J.H. Dendritic spines provide cognitive resilience against Alzheimer’s disease.Ann. Neurol. 2017; 82: 602-614Crossref PubMed Scopus (62) Google Scholar). Overall, candidate genes nominated by studies in the DO have the potential to greatly contribute to the understanding of mechanisms underlying complex traits in both mouse and humans. Here, we show that reduced Dlgap2 is associated with faster cognitive decline, AD and disease diagnosis, and increased neuropathology in humans across multiple brain regions and independent datasets. We also provide evidence that DLGAP2 protein abundance in brain is associated with cognitive decline. Mutant mice that lack Dlgap2, a post-synaptic density scaffolding protein, show impaired initial reversal learning, deficits in synaptic communication, and reduced dendritic spine density (Jiang-Xie et al., 2014Jiang-Xie L.F. Liao H.M. Chen C.H. Chen Y.T. Ho S.Y. Lu D.H. Lee L.J. Liou H.H. Fu W.M. Gau S.S. Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits.Mol. Autism. 2014; 5: 32Crossref PubMed Scopus (45) Google Scholar). Spine loss correlates more strongly to cognitive decline in Alzheimer’s disease than the classical neuropathological hallmarks (Dorostkar et al., 2015Dorostkar M.M. Zou C. Blazquez-Llorca L. Herms J. Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities.Acta Neuropathol. 2015; 130: 1-19Crossref PubMed Scopus (84) Google Scholar; Boros et al., 2017Boros B.D. Greathouse K.M. Gentry E.G. Curtis K.A. Birchall E.L. Gearing M. Herskowitz J.H. Dendritic spines provide cognitive resilience against Alzheimer’s disease.Ann. Neurol. 2017; 82: 602-614Crossref PubMed Scopus (62) Google Scholar; DeKosky and Scheff, 1990DeKosky S.T. Scheff S.W. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity.Ann. Neurol. 1990; 27: 457-464Crossref PubMed Scopus (1519) Google Scholar; Terry et al., 1991Terry R.D. Masliah E. Salmon D.P. Butters N. DeTeresa R. Hill R. Hansen L.A. Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment.Ann. Neurol. 1991; 30: 572-580Crossref PubMed Scopus (3085) Google Scholar). However, mechanisms underlying this loss of spines are still poorly understood. Work here suggests aging mouse models—at least the DO population, in particular—may provide an important experimental system in which to begin to understand mechanisms contributing to spine loss and cognitive dysfunction in human populations. Notably, the spine phenotypes that correlate to working memory in our DO population mimic the increase in thin spine density and simultaneous reduction in stubby spines observed exclusively in patients that exhibited cognitive resistance to Alzheimer’s disease pathology (Boros et al., 2017Boros B.D. Greathouse K.M. Gentry E.G. Curtis K.A. Birchall E.L. Gearing M. Herskowitz J.H. Dendritic spines provide cognitive resilience against Alzheimer’s disease.Ann. Neurol. 2017; 82: 602-614Crossref PubMed Scopus (62) Google Scholar, Boros et al., 2019Boros B.D. Greathouse K.M. Gearing M. Herskowitz J.H. Dendritic spine remodeling accompanies Alzheimer’s disease pathology and genetic susceptibility in cognitively normal aging.Neurobiol. Aging. 2019; 73: 92-103Crossref PubMed Scopus (24) Google Scholar). As we know, genotype at Dlgap2 plays an important role in regulating cognitive decline in the DO population (Figure 1D), and Dlgap2 critically regulates spine number and morphology (Jiang-Xie et al., 2014Jiang-Xie L.F. Liao H.M. Chen C.H. Chen Y.T. Ho S.Y. Lu D.H. Lee L.J. Liou H.H. Fu W.M. Gau S.S. Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits.Mol. Autism. 2014; 5: 32Crossref PubMed Scopus (45) Google Scholar). Therefore, we hypothesize that Dlgap2 may act as a potential driver of cognitive decline and later transition to dementia via its role in mediating spine-related phenotypes. This hypothesis will need to be experimentally tested, although the work here provides an important starting point for future mechanistic studies focused on elucidating the role of Dlgap2 in cognitive decline across species. In summary, the work here identifies Dlgap2 as a potential mediator of cognitive decline in both mouse and humans and highlights the benefit of using genetically diverse mouse populations to inform mechanistic studies and identify novel candidates involved in complex human disease. Future studies will investigate the role of identified variants, precise molecular mechanisms involved in mediating cognitive decline, and the utility of Dlgap2 as a therapeutic target to promote healthy brain aging." @default.
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• W3081987135 title "Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer’s Dementia" @default.
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