•Gene-environment interactions (GxE) are important in disease pathogenesis.•Few studies have explored GxE in a genome-wide or exposome-wide manner.•Recent advances will improve identification of GxE ...interactions in humans and mice.•GxE interactions will elucidate novel disease pathways and mechanisms.•Identification of GxE interactions will facilitate personalized precision medicine.
Diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) arise from complex interactions of genetic and environmental factors, with genetic variants regulating individual responses to environmental exposures (i.e. gene-by-environment interactions). Identifying gene-by-environment interactions will be critical to fully understanding disease mechanisms and developing personalized therapeutics, though these interactions are still poorly understood and largely under-studied. Candidate gene approaches have shown that known disease risk variants often regulate response to environmental factors. However, recent improvements in exposome- and genome-wide association and interaction studies in humans and mice are enabling discovery of novel genetic variants and pathways that predict response to a variety of environmental factors. Here, we highlight recent approaches and ongoing developments in human and rodent studies to identify genetic modulators of environmental factors using AD and PD as exemplars. Identifying gene-by-environment interactions in disease will be critical to developing personalized intervention strategies and will pave the way for precision medicine.
Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the ...development of Alzheimer's disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Plasticity of intrinsic excitability underlies hippocampal learning and memory.•Impaired intrinsic plasticity is a feature of aging and Alzheimer’s disease (AD).•We have an incomplete understanding ...intrinsic plasticity in memory, aging and AD.•Future studies may facilitate therapeutically targeting intrinsic excitability.
Plasticity of intrinsic neuronal excitability facilitates learning and memory across multiple species, with aberrant modulation of this process being linked to the development of neurological symptoms in models of cognitive aging and Alzheimer’s disease. Learning-related increases in intrinsic excitability of neurons occurs in a variety of brain regions, and is generally thought to promote information processing and storage through enhancement of synaptic throughput and induction of synaptic plasticity. Experience-dependent changes in intrinsic neuronal excitability rely on activity-dependent gene expression patterns, which can be influenced by genetic and environmental factors, aging, and disease. Reductions in baseline intrinsic excitability, as well as aberrant plasticity of intrinsic neuronal excitability and in some cases pathological hyperexcitability, have been associated with cognitive deficits in animal models of both normal cognitive aging and Alzheimer’s disease. Genetic factors that modulate plasticity of intrinsic excitability likely underlie individual differences in cognitive function and susceptibility to cognitive decline. Thus, targeting molecular mediators that either control baseline intrinsic neuronal excitability, subserve learning-related intrinsic neuronal plasticity, and/or promote resilience may be a promising therapeutic strategy for maintaining cognitive function in aging and disease. In this review, we discuss the complementary relationship between intrinsic excitability and learning, with a particular focus on how this relationship varies as a function of age, disease state, and genetic make-up, and how targeting these factors may help to further elucidate our understanding of the role of intrinsic excitability in cognitive function and cognitive decline.
An individual’s genetic makeup plays a large role in determining susceptibility to Alzheimer’s disease (AD) but has largely been ignored in preclinical studies. To test the hypothesis that ...incorporating genetic diversity into mouse models of AD would improve translational potential, we combined a well-established mouse model of AD with a genetically diverse reference panel to generate mice that harbor identical high-risk human mutations but differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of human AD mutations on both cognitive and pathological phenotypes. We then validate this complex AD model by demonstrating high degrees of genetic, transcriptomic, and phenotypic overlap with human AD. Overall, work here both introduces a novel AD mouse population as an innovative and reproducible resource for the study of mechanisms underlying AD and provides evidence that preclinical models incorporating genetic diversity may better translate to human disease.
•Genetically diverse AD mouse models parallel complexity of human AD•Comparative analyses identify the C56BL/6J background strain as resilient•Reproducible AD mouse lines and cognitive assays valuable for preclinical studies•Resource design serves as blueprint for improved models of polygenic diseases
Neuner et al. describe the generation and validation of the AD-BXDs, the first reproducible set of AD mouse models incorporating genetic diversity. These models recapitulate aspects of human AD and provide a new resource to identify genes and pathways associated with risk and resilience to AD.
The goal of this review article is to provide a resource for longitudinal studies, using animal models, directed at understanding and modifying the relationship between cognition and brain structure ...and function throughout life. We propose that forthcoming longitudinal studies will build upon a wealth of knowledge gleaned from prior cross-sectional designs to identify early predictors of variability in cognitive function during aging, and characterize fundamental neurobiological mechanisms that underlie the vulnerability to, and the trajectory of, cognitive decline. Finally, we present examples of biological measures that may differentiate mechanisms of the cognitive reserve at the molecular, cellular, and network level.
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•Proteomics detects 36 hippocampal proteins associated with AD and normal aging memory deficits.•Pathway analysis highlights HDAC4 as global regulator of memory deficits.•103 proteins ...differ specifically in AD mice with intact vs impaired memory.•Pathway analysis indicates disease-specific involvement of REST and Gi signaling.•Publically available proteomics resource for hypothesis generation and testing.
Alzheimer’s disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of normal aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC–MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., GRIA1, GRM3, and SYN1), were altered in both normal aging and AD. Pathway analysis highlighted HDAC4 as a regulator of observed protein changes in both genotypes and identified the REST epigenetic regulatory pathway and Gi intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins APOE and CLU. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD.
Individuals who maintain cognitive function despite high levels of Alzheimer’s disease (AD)-associated pathology are said to be ‘resilient’ to AD. Identifying mechanisms underlying resilience ...represents an exciting therapeutic opportunity. Human studies have identified a number of molecular and genetic factors associated with resilience, but the complexity of these cohorts prohibits a complete understanding of which factors are causal or simply correlated with resilience. Genetically and phenotypically diverse mouse models of AD provide new and translationally relevant opportunities to identify and prioritize new resilience mechanisms for further cross-species investigation. This review will discuss insights into resilience gained from both human and animal studies and highlight future approaches that may help translate these insights into therapeutics designed to prevent or delay AD-related dementia.
Some individuals retain cognitive function despite high levels of Alzheimer’s disease (AD) pathology. Understanding the biology behind this form of ‘AD resilience’ may lead to opportunities for therapeutic development.Human genetic studies and postmortem analyses have identified a number of factors associated with cognitive resilience to AD pathology, including overall maintenance of synapse structure and candidate molecular mediators (e.g., REST, NRN1, among others).Genetically and phenotypically diverse mouse models of AD provide new and translationally relevant opportunities to identify and prioritize new resilience mechanisms.Approaches integrating results from both human and mouse studies will provide an effective path toward the development of therapeutics promoting resilience in susceptible human populations.
Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis ...(RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear.
This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment.
PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways.
These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Identifying genetic factors that modify an individual's susceptibility to cognitive decline in aging is critical to understanding biological processes involved and mitigating risk associated with a ...number of age‐related disorders. Recently, heterochromatin protein 1 binding protein 3 (Hp1bp3) was identified as a mediator of cognitive aging. Here, we provide a mechanistic explanation for these findings and show that targeted knockdown of Hp1bp3 in the hippocampus by 50%–75% is sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and Alzheimer's disease brains. Specifically, neuroinflammatory‐related pathways become activated following Hp1bp3 knockdown in combination with a robust decrease in genes involved in synaptic activity and neuronal function. To test the hypothesis that Hp1bp3 mediates susceptibility to cognitive deficits via a role in neuronal excitability, we performed slice electrophysiology demonstrate transcriptional changes after Hp1bp3 knockdown manifest functionally as a reduction in hippocampal neuronal intrinsic excitability and synaptic plasticity. In addition, as Hp1bp3 is a known mediator of miRNA biogenesis, here we profile the miRNA transcriptome and identify mir‐223 as a putative regulator of a portion of observed mRNA changes, particularly those that are inflammatory‐related. In summary, work here identifies Hp1bp3 as a critical mediator of aging‐related changes at the phenotypic, cellular, and molecular level and will help inform the development of therapeutics designed to target either Hp1bp3 or its downstream effectors in order to promote cognitive longevity.
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