Biology subjects

Neuner, S. M.

Publications and source records attributed to Neuner, S. M..

6 recordsLinked to original sources

bioRxiv2022

Conserved cell-type specific signature of resilience to Alzheimer's disease nominates role for excitatory cortical neurons

Alzheimers disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to "cognitive resilience" to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

neuroscience↗

bioRxiv2022

Hypothalamic gene network dysfunction is associated with cognitive decline and body weight loss in Alzheimer's disease mice

Recent studies, both clinical and experimental, indicate that many neurodegenerative disorders including Alzheimers disease (AD) often display coexisting metabolic dysfunctions, which may exacerbate neurological symptoms. The hypothalamus is a brain region highly involved in maintaining metabolic and other homeostatic processes and is known to be involved in the etiology of AD, although the role of hypothalamic dysfunction in the onset, progression, and severity of AD is poorly understood. In this study, we demonstrate that our new model of genetic diversity in AD, the AD-BXDs, exhibits non-cognitive symptoms consistent with hypothalamic dysfunction and examined hypothalamic bulk RNA sequencing data in the AD-BXD panel to investigate how the AD transgene impacts gene expression profiles in the hypothalamus. Mostly notably, we identified strong neuroinflammatory signatures from the hypothalamus in the AD-BXDs as early as six months of age. A functionally unknown WGCNA module showed correlation to female body weight and contextual fear acquisition. Eigengene expression of microglial/macrophagic modules and their hub gene expressions were correlated to cognitive phenotypes. From these analyses, we nominated Plek and Laptm5 as new targets to attenuate neuroinflammation in AD.

neuroscience↗

bioRxiv2019

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s 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 Alzheimers 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 determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD-affected brain, to describe its subcellular localization, and to evaluate its molecular function. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with {beta}-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 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 {beta}-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral {beta}-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. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both {beta}-amyloid pathology and cognition.

neuroscience↗

bioRxiv2019

Genetic background modifies CNS-mediated sensorimotor decline in the AD-BXD mouse population

Many patients with Alzheimers dementia also exhibit non-cognitive symptoms such as sensorimotor deficits, which can precede the onset of the hallmark cognitive deficits and significantly impact daily activities and an individuals ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and the relationship between sensorimotor and cognitive decline remain 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 Alzheimers disease, the AD-BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD-BXDs and their relationship to cognitive decline in these mice. We found that both age- and AD-related declines in coordination, balance, and vestibular function vary significantly across the panel, indicating that genetic background strongly influences the expressivity of the familial AD mutations used in the AD-BXD panel and their impact on motor function. Further, we found that motor decline is not associated withcognitive decline in either AD or aging, suggesting that sensorimotor deficits in AD occur - in part - through distinct mechanisms. Overall, the results presented here 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.

neuroscience↗

bioRxiv2019

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 2 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 mRNA and protein 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 intronic deletion located 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 mRNA and protein. 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 as 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.

genetics↗

bioRxiv2017

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

Identifying genes that modify symptoms of Alzheimers disease (AD) will provide novel therapeutic strategies to prevent, cure or delay AD. To discover genetic modifiers of AD, we combined a mouse model of AD with a genetically diverse reference panel to generate F1 mice harboring identical high-risk human AD mutations but which differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of causal human AD mutations and validate this panel as an AD model by demonstrating a high degree of phenotypic, transcriptomic, and genetic overlap with human AD. Genetic mapping was used to identify candidate modifiers of cognitive deficits and amyloid pathology, and viral-mediated knockdown was used to functionally validate Trpc3 as a modifier of AD. Overall, work here introduces a humanized mouse population as an innovative and reproducible resource for the study of AD and identifies Trpc3 as a novel therapeutic target.\n\nHighlightsO_LINew transgenic mouse population enables mapping of AD risk and resilience factors\nC_LIO_LITranscriptomic and phenotypic profiles in diverse AD mice parallel those in humans\nC_LIO_LIApoe genotype and expression correlate with cognitive symptoms in mice\nC_LIO_LITrpc3 is a novel target to reduce amyloid load and cognitive symptoms in AD\nC_LI

genetics↗