Browsing by Subject "Amyloid plaque"

Now showing 1 - 6 of 6
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    Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations
    (Rockefeller University, 2024) Cadiz, Mika P.; Gibson, Katelin A.; Todd, Kennedi T.; Nascari, David G.; Massa, Nashali; Lilley, Meredith T.; Olney, Kimberly C.; Al-Amin, Md Mamun; Jiang, Hong; Holtzman, David M.; Fryer, John D.; Medical and Molecular Genetics, School of Medicine
    Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy.
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    Alois Alzheimer: His Life and Times
    (Wiley, 2007-01) Goedert, Michel; Ghetti, Bernardino; Pathology and Laboratory Medicine, School of Medicine
    Between national unification and World War I, Germany was preeminent in many areas of science and medicine. Alois Alzheimer, who lived during this period, was one of the founders of the field of neuropathology. His name will always be linked with the form of dementia that he described 100 years ago. Here we mark this anniversary by discussing Alzheimer's contributions to dementia research in the context of his life and times.
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    Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis
    (Springer Nature, 2024-05-11) Kim, Byungwook; Dabin, Luke Child; Tate, Mason Douglas; Karahan, Hande; Sharify, Ahmad Daniel; Acri, Dominic J.; Al-Amin, Md Mamun; Philtjens, Stéphanie; Smith, Daniel Curtis; Wijeratne, H. R. Sagara; Park, Jung Hyun; Jucker, Mathias; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-β (Aβ) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.
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    IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease
    (Springer Nature, 2019-04) Gu, Huiying; Kirchhein, Yvonne; Zhu, Timothy; Zhao, Gang; Peng, Hongjun; Du, Eileen; Liu, Junyi; Mastrianni, James A.; Farlow, Martin R.; Dodel, Richard; Du, Yansheng; Neurology, School of Medicine
    Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aβ autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Sträussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120 days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases.
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    Pathways to dementia: genetic predictors of cognitive and brain imaging endophenotypes in Alzheimer's disease
    (2014-01-03) Ramanan, Vijay K; Saykin, Andrew J.; Foroud, Tatiana; Herbert, Brittney-Shea; McDonald, Brenna C.; Shen, Li
    Alzheimer's disease (AD) is a national priority, with nearly six million Americans affected at an annual cost of $200 billion and no available cure. A better understanding of the mechanisms underlying AD is crucial to combat its high and rising incidence and burdens. Most cases of AD are thought to have a complex etiology with numerous genetic and environmental factors influencing susceptibility. Recent genome-wide association studies (GWAS) have confirmed roles for several hypothesized genes and have discovered novel loci associated with disease risk. However, most GWAS-implicated genetic variants have displayed modest individual effects on disease risk and together leave substantial heritability and pathophysiology unexplained. As a result, new paradigms focusing on biological pathways have emerged, drawing on the hypothesis that complex diseases may be influenced by collective effects of multiple variants – of a variety of effect sizes, directions, and frequencies – within key biological pathways. A variety of tools have been developed for pathway-based statistical analysis of GWAS data, but consensus approaches have not been systematically determined. We critically review strategies for genetic pathway analysis, synthesizing extant concepts and methodologies to guide application and future development. We then apply pathway-based approaches to complement GWAS of key AD-related endophenotypes, focusing on two early, hallmark features of disease, episodic memory impairment and brain deposition of amyloid-β. Using GWAS and pathway analysis, we confirmed the association of APOE (apolipoprotein E) and discovered additional genetic modulators of memory functioning and amyloid-β deposition in AD, including pathways related to long-term potentiation, cell adhesion, inflammation, and NOTCH signaling. We also identified genetic associations to amyloid-β deposition that have classically been understood to mediate learning and memory, including the BCHE gene and signaling through the epidermal growth factor receptor. These findings validate the use of pathway analysis in complex diseases and illuminate novel genetic mechanisms of AD, including several pathways at the intersection of disease-related pathology and cognitive decline which represent targets for future studies. The complexity of the AD genetic architecture also suggests that biomarker and treatment strategies may require simultaneous targeting of multiple pathways to effectively combat disease onset and progression.
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    The bidirectional lung brain-axis of amyloid-β pathology: ozone dysregulates the peri-plaque microenvironment
    (Oxford University Press, 2023) Greve, Hendrik J.; Dunbar, August L.; Garza Lombo, Carla; Ahmed, Chandrama; Thang, Morrent; Messenger, Evan J.; Mumaw, Christen L.; Johnson, James A., Jr.; Kodavanti, Urmila P.; Oblak, Adrian L.; Block, Michelle L.; Pharmacology and Toxicology, School of Medicine
    The mechanisms underlying how urban air pollution affects Alzheimer's disease (AD) are largely unknown. Ozone (O3) is a reactive gas component of air pollution linked to increased AD risk, but is confined to the respiratory tract after inhalation, implicating the peripheral immune response to air pollution in AD neuropathology. Here, we demonstrate that O3 exposure impaired the ability of microglia, the brain's parenchymal immune cells, to associate with and form a protective barrier around Aβ plaques, leading to augmented dystrophic neurites and increased Aβ plaque load. Spatial proteomic profiling analysis of peri-plaque proteins revealed a microenvironment-specific signature of dysregulated disease-associated microglia protein expression and increased pathogenic molecule levels with O3 exposure. Unexpectedly, 5xFAD mice exhibited an augmented pulmonary cell and humoral immune response to O3, supporting that ongoing neuropathology may regulate the peripheral O3 response. Circulating HMGB1 was one factor upregulated in only 5xFAD mice, and peripheral HMGB1 was separately shown to regulate brain Trem2 mRNA expression. These findings demonstrate a bidirectional lung-brain axis regulating the central and peripheral AD immune response and highlight this interaction as a potential novel therapeutic target in AD.