Pursuit of precision medicine: Systems biology approaches in Alzheimer\u27s disease mouse models.

Alzheimer\u27s disease (AD) is a complex disease that is mediated by numerous factors and manifests in various forms. A systems biology approach to studying AD involves analyses of various body systems, biological scales, environmental elements, and clinical outcomes to understand the genotype to phenotype relationship that potentially drives AD development. Currently, there are many research investigations probing how modifiable and nonmodifiable factors impact AD symptom presentation. This review specifically focuses on how imaging modalities can be integrated into systems biology approaches using model mouse populations to link brain level functional and structural changes to disease onset and progression. Combining imaging and omics data promotes the classification of AD into subtypes and paves the way for precision medicine solutions to prevent and treat AD

Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging.

Identifying genetic factors that modify an individual\u27s 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\u27s 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

Genetic background modifies CNS-mediated sensorimotor decline in the AD-BXD mouse model of genetic diversity in Alzheimer\u27s disease.

Many patients with Alzheimer\u27s dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual\u27s ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer\u27s disease, the AD-BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD-BXDs and the relationship to cognitive decline in these mice. We found that age- and AD-related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD-BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging- and AD-related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD-related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease

Translational approaches to understanding resilience to Alzheimer\u27s disease.

Individuals who maintain cognitive function despite high levels of Alzheimer\u27s disease (AD)-associated pathology are said to be \u27resilient\u27 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

Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains.

The speed and scope of cognitive deterioration in Alzheimer\u27s disease is highly associated with the advancement of tau neurofibrillary lesions across brain networks. We tested whether the rate of tau propagation is a heritable disease trait in a large, well-characterized cohort of genetically divergent mouse strains. Using an AAV-based model system, P301L-mutant human tau (hTau) was introduced into the entorhinal cortex of mice derived from 18 distinct lines. The extent of tau propagation was measured by distinguishing hTau-producing cells from neurons that were recipients of tau transfer. Heritability calculation revealed that 43% of the variability in tau spread was due to genetic variants segregating across background strains. Strain differences in glial markers were also observed, but did not correlate with tau propagation. Identifying unique genetic variants that influence the progression of pathological tau may uncover novel molecular targets to prevent or slow the pace of tau spread and cognitive decline

Leveraging genetic diversity in mice to inform individual differences in brain microstructure and memory.

In human Alzheimer\u27s disease (AD) patients and AD mouse models, both differential pre-disease brain features and differential disease-associated memory decline are observed, suggesting that certain neurological features may protect against AD-related cognitive decline. The combination of these features is known as brain reserve, and understanding the genetic underpinnings of brain reserve may advance AD treatment in genetically diverse human populations. One potential source of brain reserve is brain microstructure, which is genetically influenced and can be measured with diffusion MRI (dMRI). To investigate variation of dMRI metrics in pre-disease-onset, genetically diverse AD mouse models, we utilized a population of genetically distinct AD mice produced by crossing the 5XFAD transgenic mouse model of AD to 3 inbred strains (C57BL/6J, DBA/2J, FVB/NJ) and two wild-derived strains (CAST/EiJ, WSB/EiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI) to probe neural microanatomy in 83 regions of interest (ROIs). At 5 months of age, these mice underwent contextual fear conditioning (CFC). Strain had a significant effect on dMRI measures in most ROIs tested, while far fewer effects of sex, sex*strain interactions, or strain*sex*5XFAD genotype interactions were observed. A main effect of 5XFAD genotype was observed in only 1 ROI, suggesting that the 5XFAD transgene does not strongly disrupt neural development or microstructure of mice in early adulthood. Strain also explained the most variance in mouse baseline motor activity and long-term fear memory. Additionally, significant effects of sex and strain*sex interaction were observed on baseline motor activity, and significant strain*sex and sex*5XFAD genotype interactions were observed on long-term memory. We are the first to study the genetic influences of brain microanatomy in genetically diverse AD mice. Thus, we demonstrated that strain is the primary factor influencing brain microstructure in young adult AD mice and that neural development and early adult microstructure are not strongly altered by the 5XFAD transgene. We also demonstrated that strain, sex, and 5XFAD genotype interact to influence memory in genetically diverse adult mice. Our results support the usefulness of the 5XFAD mouse model and convey strong relationships between natural genetic variation, brain microstructure, and memory

Cognitive Reserve in Model Systems for Mechanistic Discovery: The Importance of Longitudinal Studies.

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

Identifying the molecular systems that influence cognitive resilience to Alzheimer\u27s disease in genetically diverse mice.

Individual differences in cognitive decline during normal aging and Alzheimer\u27s disease (AD) are common, but the molecular mechanisms underlying these distinct outcomes are not fully understood. We utilized a combination of genetic, molecular, and behavioral data from a mouse population designed to model human variation in cognitive outcomes to search for the molecular mechanisms behind this population-wide variation. Specifically, we used a systems genetics approach to relate gene expression to cognitive outcomes during AD and normal aging. Statistical causal-inference Bayesian modeling was used to model systematic genetic perturbations matched with cognitive data that identified astrocyte and microglia molecular networks as drivers of cognitive resilience to AD. Using genetic mapping, we identifie

Genetic background influences the 5XFAD Alzheimer\u27s disease mouse model brain proteome.

There is an urgent need to improve the translational validity of Alzheimer’s disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non- transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease—neuronal synapse/signaling and lysosome/stress response—were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight.

BACKGROUND/OBJECTIVE: As the obesity epidemic continues, the understanding of macronutrient influence on central nervous system function is critical for understanding diet-induced obesity and potential therapeutics, particularly in light of the increased sugar content in processed foods. Previous research showed mixed effects of sucrose feeding on body weight gain but has yet to reveal insight into the impact of sucrose on hypothalamic functioning. Here, we explore the impact of liquid sucrose feeding for 12 weeks on body weight, body composition, caloric intake, and hypothalamic AgRP neuronal function and synaptic plasticity. METHODS: Patch-clamp electrophysiology of hypothalamic AgRP neurons, metabolic phenotyping and food intake were performed on C57BL/6J mice. RESULTS: While mice given sugar-sweetened water do not gain significant weight, they do show subtle differences in body composition and caloric intake. When given sugar-sweetened water, mice show similar alterations to AgRP neuronal excitability as in high-fat diet obese models. Increased sugar consumption also primes mice for increased caloric intake and weight gain when given access to a HFD. CONCLUSIONS: Our results show that elevated sucrose consumption increased activity of AgRP neurons and altered synaptic excitability. This may contribute to obesity in mice and humans with access to more palatable (HFD) diets