Browsing by Subject "APOE4"

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    APOE4 Drives Impairment in Astrocyte-Neuron Coupling in Alzheimer's Disease and Works Through Mechanisms in Early Disease to Influence Pathology
    (2023-05) Brink, Danika Marie Tumbleson; Lamb, Bruce; Bissel, Stephanie; Herbert, Brittney-Shea; Landreth, Gary; Puntambekar, Shweta; Saykin, Andrew; Zhang, Chi
    Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in progressive memory loss, brain atrophy, and eventual death. AD pathology is characterized by the accumulation of neurotoxic amyloid-beta (Aβ) plaques, synapse loss, neurofibrillary tangles (NFTs), and neurodegeneration. The APOE4 allele is associated with a 3-fold increased risk for AD and results in increased Aβ plaque deposition, reduced Aβ clearance, and reduced synaptic plasticity. Although APOE expression is upregulated in microglia in AD, APOE is expressed primarily by astrocytes in the CNS. It is not well understood how astrocytic APOE drives the mechanisms that result in worsened AD outcomes. Here, digital spatial profiling and bioinformatics data suggest that APOE4 causes transcriptional dysregulation in early AD and may disrupt neuronal processes via astrocytes. Whole transcriptome data from plaque and non-plaque regions in the cortices and hippocampus of 4- and 8-month-old AD model mice expressing humanized APOE4/4 or APOE3/3 (control) were analyzed. Transcriptional dysregulation was increased in APOE4/4 AD mice compared to that in APOE3/3 at 4 but not 8 months of age, suggesting that early dysregulation of APOE4-driven disease mechanisms may shape degenerative outcomes in late-stage AD. Additionally, APOE4/4 potentially functions via plaque-independent mechanisms to influence neuronal function in early AD before the onset of pathology. Single-nuclei RNA sequencing data were obtained from human post-mortem astrocytes and the bioinformatic analyses revealed a novel astrocyte subtype that highly expresses several top genes involved in functional alterations associated with APOE4, including neuronal generation, development, and differentiation, and synaptic transmission and organization. Overall, our findings indicate that APOE4 may drive degenerative outcomes through the presented astrocyte candidate pathways. These pathways represent potential targets for investigations into early intervention strategies for APOE4/4 patients.
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    In vivo validation of late-onset Alzheimer's disease genetic risk factors
    (bioRxiv, 2023-12-24) Sasner, Michael; Preuss, Christoph; Pandey, Ravi S.; Uyar, Asli; Garceau, Dylan; Kotredes, Kevin P.; Williams, Harriet; Oblak, Adrian L.; Lin, Peter Bor-Chian; Perkins, Bridget; Soni, Disha; Ingraham, Cindy; Lee-Gosselin, Audrey; Lamb, Bruce T.; Howell, Gareth R.; Carter, Gregory W.; Radiology and Imaging Sciences, School of Medicine
    Introduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. Results: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. Discussion: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.
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    Molecular and Synaptic Signatures in Mouse Models of Late‐Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology
    (Wiley, 2025-01-03) Oblak, Adrian L.; Pharmacology and Toxicology, School of Medicine
    Background: MODEL‐AD (Model Organism Development and Evaluation for Late‐onset AD) is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant genetic risk factors. Models expressing human‐relevant risk genetic risk factors are expected to better phenocopy LOAD than widely used transgenic models. Method: Here, two genetic risk factors APOE4 and Trem2*R47H, were incorporated into C57BL/6J (B6) mice along with humanized amyloid‐beta to produce the LOAD2 model. LOAD2 and control mice were aged up to 24 months with some being provided in the absence or presence of normal chow or a high fat/high sugar diet (LOAD2 HFD) from two months of age. A phenotyping pipeline was employed to evaluate disease outcomes observed in human patients, including in vivo imaging, brain and blood biomarker and cytokine analyses, multi‐omics (transcriptomics and proteomics), neuropathology and behavior. Result: By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2 HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble AΒ42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease‐relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age‐dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2 HFD mice also showed a learning deficit based on a Touchscreen cognitive assay. Conclusion: Despite the absence of hallmark amyloid and Tau pathologies, collectively these data support the use of LOAD2 HFD mice reveal this model as important for preclinical studies that target other features of LOAD independent of amyloid and tau.