Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model DOI Creative Commons

Wenqiang Chen,

Qian Huang,

Ekaterina Lazdon

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(21)

Опубликована: Май 15, 2023

Brain insulin signaling controls peripheral energy metabolism and plays a key role in the regulation of mood cognition. Epidemiological studies have indicated strong connection between type 2 diabetes (T2D) neurodegenerative disorders, especially Alzheimer’s disease (AD), linked via dysregulation signaling, i.e., resistance. While most focused on neurons, here, we aim to understand astrocytes, glial cell highly implicated AD pathology progression. To this end, created mouse model by crossing 5xFAD transgenic mice, well-recognized that expresses five familial mutations, with mice carrying selective, inducible receptor (IR) knockout astrocytes (iGIRKO). We show age 6 mo, iGIRKO/5xFAD exhibited greater alterations nesting, Y-maze performance, fear response than those transgenes alone. This was associated increased Tau (T231) phosphorylation, Aβ plaque size, association plaques cerebral cortex as assessed using tissue CLARITY brain mice. Mechanistically, vitro IR primary resulted loss reduced ATP production glycolic capacity, impaired uptake both basal insulin-stimulated states. Thus, an important control uptake, thereby contributing pathology, highlighting potential importance targeting site for therapeutics patients T2D AD.

Язык: Английский

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol DOI Creative Commons
Hao Wang, Joshua A. Kulas, Chao Wang

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(33)

Опубликована: Авг. 12, 2021

Significance The accumulation of amyloid β (Aβ) in the brain appears to be a necessary event pathogenesis Alzheimer’s disease (AD). However, processes linked endogenous regulation Aβ production are still not completely understood. Here, authors show that neurons is tightly regulated by cholesterol synthesis and apoE transport from astrocytes. study provides molecular context for understanding why it correlates with AD. tight suggests may perform an important cellular function. A complete mechanism likely predict whether selective removal has potential therapeutic benefit.

Язык: Английский

Процитировано

235
Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise DOI
Fei Yin

FEBS Journal, Год журнала: 2022, Номер 290(6), С. 1420 - 1453

Опубликована: Янв. 8, 2022

Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, a lack of disease‐modifying therapeutics. While the abnormal accumulation lipids was described in very first report AD neuropathology, it not until recent decades that lipid dyshomeostasis became focus research. Clinically, lipidomic metabolomic studies have consistently shown alterations levels various classes emerging early stages brains. Mechanistically, discovery research revealed multifaceted interactions between metabolism key pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, myelin degeneration. In present review, converging evidence defining summarized, followed by discussions on which contributes to pathogenesis modifies risk. Furthermore, lipid‐targeting therapeutic strategies, modification their efficacy stage, ApoE status, metabolic vascular profiles, are reviewed.

Язык: Английский

Процитировано

196
Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

и другие.

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

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Язык: Английский

Процитировано

173
Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects DOI Creative Commons
Femke M. Feringa, Rik van der Kant

Frontiers in Aging Neuroscience, Год журнала: 2021, Номер 13

Опубликована: Июнь 24, 2021

While the central nervous system compromises 2% of our body weight, it harbors up to 25% body's cholesterol. Cholesterol levels in brain are tightly regulated for physiological function, but mounting evidence indicates that excessive cholesterol accumulates Alzheimer's disease (AD), where may drive AD-associated pathological changes. This seems especially relevant late-onset AD, as several major genetic risk factors functionally associated with metabolism. In this review we discuss different systems maintain metabolism healthy brain, and how dysregulation these processes can lead, or contribute to, disease. We will also AD-risk genes might impact downstream AD pathology. Finally, address outstanding questions field recent technical advances CRISPR/Cas9-gene editing induced pluripotent stem cell (iPSC)-technology aid study problems.

Язык: Английский

Процитировано

172
The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored DOI Creative Commons
Sidhanth Chandra, Sangram S. Sisodia, Robert Vassar

и другие.

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Фев. 1, 2023

Alzheimer's disease (AD), the most common cause of dementia, results in a sustained decline cognition. There are currently few effective modifying therapies for AD, but insights into mechanisms that mediate onset and progression may lead to new, therapeutic strategies. Amyloid beta oligomers plaques, tau aggregates, neuroinflammation play critical role neurodegeneration impact clinical AD progression. The upstream modulators these pathological features have not been fully clarified, recent evidence indicates gut microbiome (GMB) an influence on therefore human patients. In this review, we summarize studies identified alterations GMB correlate with pathophysiology patients mouse models. Additionally, discuss findings manipulations models potential GMB-targeted therapeutics AD. Lastly, diet, sleep, exercise as modifiers relationship between conclude future directions recommendations further topic.

Язык: Английский

Процитировано

166
Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity DOI Creative Commons
Matheus B. Victor,

Noelle Leary,

Xochitl Luna

и другие.

Cell stem cell, Год журнала: 2022, Номер 29(8), С. 1197 - 1212.e8

Опубликована: Авг. 1, 2022

Язык: Английский

Процитировано

150
The role of high cholesterol in age-related COVID19 lethality DOI Creative Commons
Hao Wang, Zixuan Yuan, Mahmud Arif Pavel

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2020, Номер unknown

Опубликована: Май 10, 2020

ABSTRACT Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan, China 2019. The notably elderly and those with underlying chronic conditions. A molecular mechanism that explains why the are vulnerable children resistant largely unknown. Here we show loading cells cholesterol from blood serum using transport protein apolipoprotein E (apoE) enhances entry of pseudotyped SARS-CoV-2 infectivity virion. Super resolution imaging point high shows almost twice total number endocytic points. Cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to site where presumably docks efficiently exploit into cell. Furthermore, producing virus, optimally positions furin for priming SARS-CoV-2, more infectious virion improved binding ACE2 receptor. In vivo, age fat diet induces up 40% trafficking sites lung tissue mice. We propose component COVID19 severity based on level sensitivity cholesterol. Molecules reduce or disrupt localization viral points producer cells, may obese patients.

Язык: Английский

Процитировано

140
Brain cell type-specific cholesterol metabolism and implications for learning and memory DOI
Dingfeng Li,

Juan Zhang,

Qiang Liu

и другие.

Trends in Neurosciences, Год журнала: 2022, Номер 45(5), С. 401 - 414

Опубликована: Фев. 17, 2022

Язык: Английский

Процитировано

92
Machine Learning for Dementia Prediction: A Systematic Review and Future Research Directions DOI Creative Commons
Ashir Javeed, Ana Luiza Dallora, Johan Berglund

и другие.

Journal of Medical Systems, Год журнала: 2023, Номер 47(1)

Опубликована: Фев. 1, 2023

Nowadays, Artificial Intelligence (AI) and machine learning (ML) have successfully provided automated solutions to numerous real-world problems. Healthcare is one of the most important research areas for ML researchers, with aim developing disease prediction systems. One detection problems that AI researchers focused on dementia using methods. Numerous diagnostic systems based techniques early been proposed in literature. Few systematic literature reviews (SLR) conducted past. However, these SLR a single type data modality dementia. Hence, purpose this study conduct comprehensive evaluation ML-based considering different types modalities such as images, clinical-features, voice data. We collected articles from 2011 2022 keywords dementia, learning, feature selection, modalities, The selected were critically analyzed discussed. It was observed image driven models yields promising results terms compared other i.e., clinical feature-based Furthermore, highlighted limitations previously methods presented future directions overcome limitations.

Язык: Английский

Процитировано

90
Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment DOI

Shuyao Ruan,

Jiaqi Li, Hang Ruan

и другие.

Journal of Controlled Release, Год журнала: 2024, Номер 366, С. 712 - 731

Опубликована: Янв. 21, 2024

Язык: Английский

Процитировано

32