Using Genetic Diversity to Understand Susceptibility to Cognitive Decline in Aging and Alzheimer’s Disease

An individual\u27s genetic makeup plays an important role in determining susceptibility to cognitive aging and transition to dementia such as Alzheimer\u27s disease (AD). Identifying the specific genetic variants that contribute to cognitive aging and AD may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we turned to genetically diverse mice from the BXD genetic reference panel (GRP) to overcome some of the barriers traditionally associated with human studies. Using a forward genetics screen, we first identified and validated the gene heterochromatin protein l binding protein 3 (Hp1bp3) as a novel modulator of normal cognitive aging. We then demonstrated that targeted knockdown of Hp1bp3 in the hippocampus by 50-75% was sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and AD, namely an increase in inflammatory pathways and decrease in neuronal and synaptically-localized transcripts. We also show Hp1bp3 is a translationally relevant target, as transcriptional changes induced by our targeted knockdown significantly overlapped those observed in the aging human brain. In addition, HPlBP3 itself was decreased in the hippocampus of cognitively impaired aging humans. In summary, our results suggest therapeutics designed to target either Hp1bp3 or its downstream effectors may be useful promoting cognitive longevity. We next expanded on our findings that the BXDs were variably susceptible to cognitive aging and combined the BXD GRP with a well-established transgenic mouse model of AD harboring 5 familial AD mutations, the 5XFAD model. The resulting panel, which we termed the AD-BXDs, consists of genetically diverse yet isogenic Fl mice that all harbor the same high-risk human AD mutations but who differ across the remainder of their genome. We first showed that genetic variation profoundly modified the impact of human AD mutations on both cognitive and pathological phenotypes. We then validated this complex AD model by demonstrating high degrees of genetic, transcriptomic, and phenotypic overlap with human AD. Genetic mapping was used to identify novel genomic loci that modified susceptibility or resilience to cognitive and pathological symptoms of AD. Finally, we used transcriptome profiling to identify gene networks present in the pre-symptomatic mouse brain that predict cognitive performance at an advanced age. Together, the candidates identified through these analyses highlight new potential drivers of susceptibility or resilience to AD and contribute significantly to our understanding of early, potentially causal disease mechanisms. In summary, work here highlights the utility of genetically diverse mice to elucidate mechanisms underlying complex human disease, namely cognitive aging and AD. In addition, we developed a novel AD mouse population as an innovative and reproducible resource for the study of mechanisms underlying AD. Data presented here provides convincing evidence that preclinical models incorporating genetic diversity may better translate to human disease. Due to the reproducible nature of the BXDs and resulting AD-BXDs, this approach creates substantial opportunities to develop improved models of human aging and AD as well as develop a better understanding of precise mechanisms underlying disease. Together, these resources may ultimately enable precision medicine approaches across a diverse population. Finally, our experimental design is likely to be broadly applicable to mouse models of human disease that incorporate a dominantly inherited high-risk genotype in the form of a transgene or other genetic perturbation, enhancing the general utility of results reported here

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

Identification of Pre-symptomatic Gene Signatures That Predict Resilience to Cognitive Decline in the Genetically Diverse AD-BXD Model

Across the population, individuals exhibit a wide variation of susceptibility or resilience to developing Alzheimer’s disease (AD). Identifying specific factors that promote resilience would provide insight into disease mechanisms and nominate potential targets for therapeutic intervention. Here, we use transcriptome profiling to identify gene networks present in the pre-symptomatic AD mouse brain relating to neuroinflammation, brain vasculature, extracellular matrix organization, and synaptic signaling that predict cognitive performance at an advanced age. We highlight putative drivers of these observed relationships, including Itgb2, Fcgr2b, Slc6a14, and Gper1, which represent prime targets through which to promote resilience prior to overt symptom onset. In addition, we identify a genomic region on chromosome 2 containing variants that directly modulate resilience network expression. Overall, work here highlights new potential drivers of resilience to AD and contributes significantly to our understanding of early, potentially causal, disease mechanisms

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

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

Dissemination of psychotherapy Modules for traumatized Refugees Experience gained from the Trauma Work in Crisis and Conflict Regions

Elbert T, Wilker S, Schauer M, Neuner F. Dissemination psychotherapeutischer Module für traumatisierte Geflüchtete. Erkenntnisse aus der Traumaarbeit in Krisen- und Kriegsregionen. NERVENARZT. 2017;88(1):26-33.With each additional accumulative exposure to severe and traumatic stressors, the likelihood of developing mental health problems and physical diseases increases. Displaced individuals have usually experienced a number of serious threats to health due to organized violence in their home country or attacks during the flight. Frequently, domestic violence adds additional strain to the stressors experienced. The resulting impairments in psychosocial functioning reduce the resources needed for social adjustment and integration. Social exclusion then in turn often further aggravates the existing mental health complications. For the treatment of trauma spectrum disorders, different evidence-based psychotherapies are available. In high-income countries, trained and licensed psychotherapists are typically in positions to apply such interventions; however, even an advanced system with a high capacity, such as the psychotherapeutic care offered in Germany, severely struggles to manage the demands associated with the rapid addition of hundreds of thousands of displaced people. Germany's mental healthcare system at present lacks the resources, both human and technological, to effectively manage the present demands. Systematic scientific studies in resource-poor regions of war and conflict have demonstrated that the dissemination of effective treatment to local personnel, even with limited training, results in substantial improvements in the mental health challenges within the community: Organized as a cascade model, members of the refugee community learn to identify weakened fellow citizens requiring in-depth diagnostic interviews. Educated, bilingual individuals acquainted with their country's healthcare system (e. g. nurses, teachers and social workers) receive training to conduct structured interviews and evidence-based interventions under the supervision of centrally organized licensed psychotherapists. More complex cases are referred to local psychotherapists, psychiatrists or specialized treatment centers. These humanitarian efforts are based on the convention for the protection of human rights and secure the safety, freedom and dignity of these persons

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

Identifying Mechanisms of Normal Cognitive Aging Using a Novel Mouse Genetic Reference Panel.

Developing strategies to maintain cognitive health is critical to quality of life during aging. The basis of healthy cognitive aging is poorly understood; thus, it is difficult to predict who will have normal cognition later in life. Individuals may have higher baseline functioning (cognitive reserve) and others may maintain or even improve with age (cognitive resilience). Understanding the mechanisms underlying cognitive reserve and resilience may hold the key to new therapeutic strategies for maintaining cognitive health. However, reserve and resilience have been inconsistently defined in human studies. Additionally, our understanding of the molecular and cellular bases of these phenomena is poor, compounded by a lack of longitudinal molecular and cognitive data that fully capture the dynamic trajectories of cognitive aging. Here, we used a genetically diverse mouse population (B6-BXDs) to characterize individual differences in cognitive abilities in adulthood and investigate evidence of cognitive reserve and/or resilience in middle-aged mice. We tested cognitive function at two ages (6 months and 14 months) using y-maze and contextual fear conditioning. We observed heritable variation in performance on these traits

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer\u27s disease.

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\u27s 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

Identification of a Functional Non-coding Variant in the GABAA Receptor α2 Subunit of the C57BL/6J Mouse Reference Genome: Major Implications for Neuroscience Research

GABA type-A (GABA-A) receptors containing the α2 subunit (GABRA2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of GABRA2 brain protein and mRNA in the B6J strain relative to other inbred strains, and identify and validate the causal mutation in B6J. The mutation is a single base pair deletion located in an intron adjacent to a splice acceptor site that only occurs in the B6J reference genome. The deletion became fixed in B6J between 1976 and 1991 and is now pervasive in many engineered lines, BXD strains generated after 1991, the Collaborative Cross, and the majority of consomic lines. Repair of the deletion using CRISPR-Cas9-mediated gene editing on a B6J genetic background completely restored brain levels of GABRA2 protein and mRNA. Comparison of transcript expression in hippocampus, cortex, and striatum between B6J and repaired genotypes revealed alterations in GABA-A receptor subunit expression, especially in striatum. These results suggest that naturally occurring variation in GABRA2 levels between B6J and other substrains or inbred strains may also explain strain differences in anxiety-like or alcohol and drug response traits related to striatal function. Characterization of the B6J private mutation in the Gabra2 gene is of critical importance to molecular genetic studies in neurobiological research because this strain is widely used to generate genetically engineered mice and murine genetic populations, and is the most widely utilized strain for evaluation of anxiety-like, depression-like, pain, epilepsy, and drug response traits that may be partly modulated by GABRA2 function