Harnessing Immunoproteostasis to Treat Neurodegenerative Disorders

Golde, Todd E.

doi:10.1016/j.neuron.2019.02.027

Cited by 31 publications

(40 citation statements)

References 159 publications

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“…Furthermore, the DEGs that were uniquely found in the AD mouse hippocampus were involved in “altered T cell and B cell signaling in rheumatoid arthritis,” “communication between innate and adaptive immune cells,” and “immune cell trafficking.” Consistently, the proinflammatory activity of microglia is related to behavioral alterations in AD patients and experimental models of the disease [ 26 ]. DEGs that were only found in the AD mouse blood were involved in “primary immunodeficiency signaling,” “inflammatory response,” and “lymphoid tissue structure and development.” These results provide further evidence showing the important roles of the immune system in both the brain and blood in the pathogenesis of AD [ 27 , 28 ].…”

Section: Discussionsupporting

confidence: 62%

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Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

et al. 2020

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The testing of pathological biomarkers of Alzheimer’s disease (AD), such as amyloid beta and tau, is time-consuming, expensive, and invasive. Here, we used 3xTg-AD mice to identify and validate putative novel blood transcriptome biomarkers of AD that can potentially be identified in the blood of patients. mRNA was extracted from the blood and hippocampus of 3xTg-AD and control mice at different ages and used for microarray analysis. Network and functional analyses revealed that the differentially expressed genes between AD and control mice modulated the immune and neuroinflammation systems. Five novel gene transcripts (Cdkn2a, Apobec3, Magi2, Parp3, and Cass4) showed significant increases with age, and their expression in the blood was collated with that in the hippocampus only in AD mice. We further assessed previously identified candidate biomarker genes. The expression of Trem1 and Trem2 in both the blood and brain was significantly increased with age. Decreased Tomm40 and increased Pink1 mRNA levels were observed in the mouse blood. The changes in the expression of Snca and Apoe mRNA in the mouse blood and brain were similar to those found in human AD blood. Our results demonstrated that the immune and neuroinflammatory system is involved in the pathophysiologies of aging and AD and that the blood transcriptome might be useful as a biomarker of AD.

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Section: Discussionsupporting

confidence: 62%

“…Consistently, the proinflammatory activity of microglia is related to behavioral alterations in AD patients and experimental models of the disease [26]. DEGs that were only found in the AD mouse blood were involved in "primary immunodeficiency signaling," "inflammatory response," and "lymphoid tissue [27,28].…”

Section: Discussionmentioning

confidence: 75%

Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

et al. 2020

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“…Microglia are resident immune cells in the brain that help maintain CNS homeostasis and can initiate inflammatory reactions when this homeostasis is perturbed. In AD, microglia can become chronically dysfunctional [203]. Recent genome wide association studies have identified several microglial genes that regulate AD risk, foremost among them being TREM2 [204].…”

Section: Trem2mentioning

confidence: 99%

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

Williams

Borchelt

Chakrabarty

2020

Mol Neurodegeneration

112

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One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. Humans predominantly possess three different allelic variants of APOE, termed E2, E3, and E4, with the E3 allele being the most common. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE-related genetic risk, considerable effort has been devoted towards developing cellular and animal models. Data from these models indicate that APOE4 exacerbates amyloid β plaque burden in a dose-dependent manner. and may also enhance tau pathogenesis in an isoform-dependent manner. Other studies have suggested APOE4 increases the risk of AD by mechanisms that are distinct from modulation of Aβ or tau pathology. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood. Collectively, the available studies suggest that APOE may impact multiple signaling pathways and thus investigators have sought therapeutics that would disrupt pathological functions of APOE while preserving or enhancing beneficial functions. This review will highlight some of the therapeutic strategies that are currently being pursued to target APOE4 towards preventing or treating AD and we will discuss additional strategies that holds promise for the future.

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“…Inflammation is also an important and controversial feature of AD [71, 72] as its precise role in disease progression is complex and still unknown [73]. Since BSCs contain all the cell types of the CNS they are suitable models to investigate inflammatory mechanisms in AD.…”

Section: Exploring Other Mechanisms Underlying Ad In Bscsmentioning

confidence: 99%

Organotypic brain slice cultures to model neurodegenerative proteinopathies

Croft

Futch

Moore

et al. 2019

Mol Neurodegeneration

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Organotypic slice cultures of brain or spinal cord have been a longstanding tool in neuroscience research but their utility for understanding Alzheimer’s disease (AD) and other neurodegenerative proteinopathies has only recently begun to be evaluated. Organotypic brain slice cultures (BSCs) represent a physiologically relevant three-dimensional model of the brain. BSCs support all the central nervous system (CNS) cell types and can be produced from brain areas involved in neurodegenerative disease. BSCs can be used to better understand the induction and significance of proteinopathies underlying the development and progression of AD and other neurodegenerative disorders, and in the future may serve as bridging technologies between cell culture and in vivo experiments for the development and evaluation of novel therapeutic targets and strategies. We review the initial development and general use of BSCs in neuroscience research and highlight the advantages of these cultures as an ex vivo model. Subsequently we focus on i) BSC-based modeling of AD and other neurodegenerative proteinopathies ii) use of BSCs to understand mechanisms underlying these diseases and iii) how BSCs can serve as tools to screen for suitable therapeutics prior to in vivo investigations. Finally, we will examine i) open questions regarding the use of such cultures and ii) how emerging technologies such as recombinant adeno-associated viruses (rAAV) may be combined with these models to advance translational research relevant to neurodegenerative disorders.

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Harnessing Immunoproteostasis to Treat Neurodegenerative Disorders

Cited by 31 publications

References 159 publications

Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

Organotypic brain slice cultures to model neurodegenerative proteinopathies

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