APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading DOI Creative Commons
Chanung Wang, Aishwarya Nambiar, Michael R. Strickland

и другие.

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(14)

Опубликована: Июнь 6, 2023

Alzheimer's disease (AD) is the most common cause of dementia. The APOE-ε4 allele apolipoprotein E (APOE) gene strongest genetic risk factor for late-onset AD. APOE genotype modulates effect sleep disruption on AD risk, suggesting a possible link between apoE and in pathogenesis, which relatively unexplored. We hypothesized that modifies Aβ deposition plaque-associated tau seeding spreading form neuritic plaque-tau (NP-tau) pathology response to chronic deprivation (SD) an isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with without AD-tau injection. found SD significantly increased peri-plaque NP-tau presence APOE4 but not APOE3. decreased microglial clustering around plaques aquaporin-4 (AQP4) polarization blood vessels also sleep-deprived APPPS1:E4 injected had altered behaviors compared APPPS1:E3 mice. These findings suggest critical modifier development SD.

Язык: Английский

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases DOI Creative Commons
Jian Sheng Loh, Wen Qi Mak, Li Tan

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Язык: Английский

Процитировано

274

Human microglial state dynamics in Alzheimer’s disease progression DOI Creative Commons
Na Sun, Matheus B. Victor, Yongjin Park

и другие.

Cell, Год журнала: 2023, Номер 186(20), С. 4386 - 4403.e29

Опубликована: Сен. 1, 2023

Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus transcriptomes epigenomes across 443 human subjects diverse Alzheimer's (AD) pathological phenotypes. We annotate 12 transcriptional states, including AD-dysregulated homeostatic, inflammatory, lipid-processing states. identify 1,542 AD-differentially-expressed genes, both microglia-state-specific disease-stage-specific alterations. By integrating epigenomic, transcriptomic, motif information, infer upstream regulators of cell gene-regulatory networks, enhancer-gene links, transcription-factor-driven state transitions. demonstrate that ectopic expression our predicted homeostatic-state activators induces homeostatic features in iPSC-derived microglia-like cells, while inhibiting inflammation can block inflammatory progression. Lastly, pinpoint the AD-risk genes differential their during AD Overall, provide insights underlying state-specific AD-stage-specific alterations at unprecedented resolution.

Язык: Английский

Процитировано

183

APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia DOI Creative Commons
Michael S. Haney, Róbert Pálovics, Christy Munson

и другие.

Nature, Год журнала: 2024, Номер 628(8006), С. 154 - 161

Опубликована: Март 13, 2024

Abstract Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these are highly expressed glial cells 1 . However, the relationship between glia pathology remains poorly understood. Through single-nucleus RNA sequencing brain tissue disease, we have identified a microglial state defined by expression droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant patients having APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces expression, triglyceride synthesis droplet accumulation an APOE-dependent manner. Additionally, conditioned media from droplet-containing lead to Tau phosphorylation neurotoxicity Our findings suggest link neurotoxic microglia-derived factors, potentially providing therapeutic strategies disease.

Язык: Английский

Процитировано

163

Insights into Alzheimer’s disease from single-cell genomic approaches DOI
Mitchell H. Murdock, Li‐Huei Tsai

Nature Neuroscience, Год журнала: 2023, Номер 26(2), С. 181 - 195

Опубликована: Янв. 2, 2023

Язык: Английский

Процитировано

104

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge DOI Creative Commons
Sangderk Lee, Nicholas A. Devanney, Lesley R. Golden

и другие.

Cell Reports, Год журнала: 2023, Номер 42(3), С. 112196 - 112196

Опубликована: Март 1, 2023

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept immunometabolism. Here, we combined bulk, single-cell, spatial transcriptomics cell-specific spatially resolved analyses in mice expressing human APOE to systematically address role across age, neuroinflammation, AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes APOE4 glial transcriptome, specifically subsets metabolically distinct microglia enriched brain during aging or following an inflammatory challenge. display increased Hif1α expression disrupted tricarboxylic acid (TCA) cycle are inherently pro-glycolytic, while mass spectrometry imaging highlight E4-specific response amyloid characterized by widespread alterations lipid metabolism. Taken together, our emphasize central for regulating microglial immunometabolism provide valuable, interactive resources discovery validation research.

Язык: Английский

Процитировано

96

Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications DOI Creative Commons

Jonas Cerneckis,

Hongxia Cai,

Yanhong Shi

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Апрель 26, 2024

The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable genetic engineering, can be differentiated into most somatic types. been widely applied model human development diseases, perform drug screening, develop therapies. In this review, we outline key developments iPSC field highlight immense versatility of modeling therapeutic applications. We begin by discussing pivotal discoveries that revealed potential a nucleus reprogramming led successful generation iPSCs. consider molecular mechanisms dynamics as well numerous methods available induce pluripotency. Subsequently, discuss various iPSC-based cellular models, from mono-cultures single type complex three-dimensional organoids, how these models elucidate diseases. use examples neurological disorders, coronavirus disease 2019 (COVID-19), cancer diversity disease-specific phenotypes modeled using iPSC-derived cells. also used high-throughput screening toxicity studies. Finally, process developing autologous allogeneic therapies their alleviate

Язык: Английский

Процитировано

88

Apolipoprotein E in lipid metabolism and neurodegenerative disease DOI Creative Commons
Linda Yang, Zachary M. March, Roxan A. Stephenson

и другие.

Trends in Endocrinology and Metabolism, Год журнала: 2023, Номер 34(8), С. 430 - 445

Опубликована: Июнь 24, 2023

Dysregulation of lipid metabolism has emerged as a central component many neurodegenerative diseases. Variants the transport protein, apolipoprotein E (APOE), modulate risk and resilience in several diseases including late-onset Alzheimer's disease (LOAD). Allelic variants gene, APOE, alter cells tissues have been broadly associated with other cellular systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to disease-related phenotypes consequently, attenuate impart multiple We review molecular, cellular, tissue-level alterations that arise from different APOE isoforms. These changes could help elucidate mechanisms tune resilience.

Язык: Английский

Процитировано

85

Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance DOI Creative Commons
Evgenia Salta, Orly Lazarov, Carlos P. Fitzsimons

и другие.

Cell stem cell, Год журнала: 2023, Номер 30(2), С. 120 - 136

Опубликована: Фев. 1, 2023

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, clinical data critically discuss the multicellular complexity niche relation to pathophysiology. further present roadmap toward better understanding role by probing promises caveats latest technological advancements field addressing conceptual methodological challenges ahead.

Язык: Английский

Процитировано

82

Cell type-specific roles of APOE4 in Alzheimer disease DOI
Jessica Blumenfeld, Oscar Yip, Min Joo Kim

и другие.

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(2), С. 91 - 110

Опубликована: Янв. 8, 2024

Язык: Английский

Процитировано

65

Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist DOI Creative Commons
Alexandra Litvinchuk, Jung H. Suh, Jing Guo

и другие.

Neuron, Год журнала: 2023, Номер 112(3), С. 384 - 403.e8

Опубликована: Ноя. 22, 2023

Язык: Английский

Процитировано

64