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Sleep as a window to understand and regulate Alzheimer's disease:emerging roles of thalamic reticular nucleus

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Neural Regeneration Research 2025年第6期20卷 1711-1712页

作者： Haoqi Sun Shiqian Shen Robert J.Thomas M.Brandon Westover Can Zhang Department of Neurology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Center for Translational Pain Research Department of AnesthesiaCritical Care and Pain MedicineMassachusetis General HospitalHarvard Medical SchoolBostonMAUSA Division of Pulmonary Critical Care and Sleep MedicineDepartment of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Genetics and aging Research unit McCance Center for Brain HealthMass General Institute for Neurodegenerative DiseaseDepartment of NeurologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA

Introduction:Alzheimer 's disease(AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β(Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism,showing slowed clinical decline(van Dyck et al.,2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches(Zhang, 2023).

关键词： Alzheimer inflammation hypothesis

What is the relationship between frailty and orthostatic hypotension in older adults?

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Journal of Geriatric Cardiology 2019年第3期16卷 272-279页

作者： Suleyman Emre Kocyigit Pinar Soysal Esra Ates Bulut Ali Ekrem Aydin Ozge Dokuzlar Ahmet Turan Isik unit for aging brain and dementia Department of Geriatric MedicineFaculty of MedicineDokuz Eylul UniversityIzmirTurkey Department of Geriatric Medicine Bezmialem Vakif UniversityFaculty of MedicineIstanbulTurkey

Background Frailty and orthostatic hypotension (OH),which is common in older adults,is associated with morbidity and *** relationship between them remains *** aim of the study is to determine whether there is a relationship between frailty and *** A total of 496 patients who were admitted to the geriatric clinic and underwent comprehensive geriatric assessment were retrospectively *** a cross-sectional and observational study,OH was measured by the Head-up Tilt Table test at 1,3,and 5 min (respectively,OH1,OH3,and OH5) and the frailty was measured by the Fried’s frailty *** The mean age of all patients was 75.4 ± *** prevalence of females was 69.8%.When the frail people were compared with the pre-frail and the robust ones,the frailty was associated with *** was no relationship between the groups in terms of OH1 when the pre-frail group was compared with the robust ***3 were higher in the frail group than in the pre-frail group (P 0.05).Slowness and weakness were associated with OH1 (P < 0.05),whereas the other components of the Fried’s test were *** Frailty may be a risk factor for *** 1^st min measurements of OH should be routinely evaluated in frail older adults to prevent OH-related poor outcomes.

关键词： Frail Orthostatic hypotension Pre-frail Robust

Fibrinogen’s potential role in connecting cerebrovascular abnormalities with glymphatic dysfunction in Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 203-204页

作者： Vishal Singh Arnab Choudhury Hyung Jin Ahn Department of Pharmacology Physiology and NeurosciencesRutgers-New Jersey Medical SchoolNewarkNJUSA brain Health Institute Rutgers UniversityPiscatawayNJUSA

Alzheimer’s disease(AD)stands out as the primary manifestation of age-related dementia,portraying a chronic neurodegenerative disorder distinguished by the accumulation of fibrillar amyloid-β(Aβ)plaques and neurofibrillary tangles of hyperphosphorylated ***,from a clinical standpoint,AD presents itself as a complex condition with a spectrum of dysfunctions rather than a singular pathological *** often-overlooked aspect of the disease is the presence of extensive cerebrovascular abnormalities,given that the majority of AD patients experience altered cerebral blood flow,damaged vasculature,increased microinfarcts and *** models of AD further support this observation,showing cerebrovascular dysfunction such as impaired cerebral blood flow and altered cerebrovascular reactivity(Tataryn et al.,2021;Gareau et al.,2023).

关键词： cerebrovascular dysfunction Alzheimer

Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease:baseline data and statistical analysis plan for the Lacunar Intervention Trial-2(LACI-2)(ISRCTN14911850)

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Stroke & Vascular Neurology 2023年第2期8卷 134-143页

作者： Philip M Bath Iris Mhlanga Lisa J Woodhouse Fergus Doubal Katherine Oatey Alan A Montgomery Joanna M Wardlaw LACI-Trial Investigators Stroke Trials unit University of NottinghamNottinghamUK Centre for Clinical brain Sciences UK Dementia Research Institute CentreUniversity of EdinburghEdinburghUK Edinburgh Clinical Trials unit University of EdinburghEdinburghUK Nottingham Clinical Trials unit University of NottinghamNottinghamUK

Background Cerebral small vessel disease(SVD)causes lacunar strokes(25%of all ischaemic strokes),physical frailty and cognitive impairment and vascular and mixed *** is no specific treatment to prevent progression of *** The LACunar Intervention Trial-2 is an investigator-initiated prospective randomised open-label blinded-endpoint phase II feasibility study assessing cilostazol and isosorbide mononitrate for preventing SVD *** aimed to recruit 400 patients with clinically evident lacunar ischaemic stroke and randomised to cilostazol,isosorbide mononitrate,both or neither,in addition to guideline secondary ischaemic stroke prevention,in a partial factorial *** primary outcome is feasibility of recruitment and adherence to medication;key secondary outcomes include:drug tolerability;recurrent vascular events,cognition and function at 1 year after randomisation;and safety(bleeding,falls,death).Data are number(%)and median(IQR).Results The trial commenced on 5 February 2018 and ceased recruitment on 31 May 2021 with 363 patients randomised,with the following baseline characteristics:average age 64(56.0,72.0)years,female 112(30.9%),stroke onset to randomisation 79.0(27.0,244.0)days,hypertension 267(73.6%),median blood pressures 143.0(130.0,157.0)/83.0(75.0,90.0)mm Hg,current smokers 67(18.5%),educationally achieved end of school examinations(A-level)or higher 118(32.5%),modified Rankin scale 1.0(0.0,1.0),National Institutes Health stroke scale 1.0(1.4),Montreal Cognitive Assessment 26.0(23.0,28.0)and total SVD score on brain imaging 1.0(0.0,2.0).This publication summarises the baseline data and presents the statistical analysis *** The trial is currently in follow-up which will complete on 31 May 2022 with results expected in October *** registration number ISRCTN14911850.

关键词： nitrate initiated prevention

Visualizing the microtubule-associated protein tau in the nucleus

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Science China(Life Sciences) 2014年第4期57卷 422-431页

作者： LU Jing LI Ting HE RongQiao BARTLETT Perry F GTZ Jürgen Clem Jones Centre for Ageing dementia Research Queensland Brain Institute The University of QueenslandBrisbane Institute of Biophysics Chinese Academy of Sciences

Although tau is mainly known as an axonal microtubule-associated protein,many studies indicate that it is not restricted to this subcellular *** tau’s subcellular distribution,however,is not trivial as is evident from transgenic mouse *** human tau is over-expressed,it can be immunohistochemically localized to axons and the somatodendritic domain,modeling what is found in neurodegenerative diseases such as Alzheimer’s ***,in wild-type mice,despite its abundance,tau is difficult to visualize even in the *** is even more challenging to detect this protein in the nucleus,where tau has been proposed to protect DNA from *** establish a framework for future studies into tau’s nuclear functions,we compared several methods to visualize endogenous nuclear tau in cell lines and mouse *** depending on the fixation and permeabilization protocol,we were able to detect nuclear tau in SH-SY5Y human neuroblastoma cells,we failed to do so in N2a murine neuroblastoma *** a second method we used subcellular fractionation of mouse tissue and found that in the nucleus tau is mainly present in a hypophosphorylated *** either full-length or truncated human tau was expressed,both accumulated in the cytoplasm,but were also found in the nuclear *** subcellular fractionation methods have their limitations,we finally isolated nuclei to probe for nuclear tau and found that the nuclei were free of cytoplasmic *** our analysis identifies several protocols for detecting tau in the nucleus where it is found in a less phosphorylated form.

关键词： Alzheimer's disease fractionation microtubule-associated protein neuroblastoma nucleus phosphorylation tau

High mobility group box 1 in the central nervous system:regeneration hidden beneath inflammation

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Neural Regeneration Research 2025年第1期20卷 107-115页

作者： Hanki Kim Bum Jun Kim Seungyon Koh Hyo Jin Cho Xuelian Jin Byung Gon Kim Jun Young Choi Department of brain Science Ajou University School of MedicineSuwonSouth Korea Department of Biomedical Sciences Ajou University Graduate School of MedicineSuwonSouth Korea Department of Neurology Ajou University School of MedicineSuwonSouth Korea Department of Geriatrics The Affiliated Suqian First People’s Hospital of Nanjing Medical UniversitySuqianJiangsu ProvinceChina

High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and ***-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain *** drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system *** it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system *** this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory *** targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.

关键词： central nervous system damage-associated molecular pattern ethyl pyruvate glycyrhizzin high mobility group box 1 inflammation neural stem cells neurodevelopment oligodendrocyte progenitor cells redox status regeneration

Depression following a traumatic brain injury:uncovering cytokine dysregulation as a pathogenic mechanism

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Neural Regeneration Research 2018年第10期13卷 1693-1704页

作者： Colleen N.Bodnar Josh M.Morganti Adam D.Bachstetter Spinal Cord & brain Injury Research Center University of Kentucky Department of Neuroscience University of Kentucky Sanders-Brown Center on aging University of Kentucky

A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.

关键词： concussion major-depressive disorder chronic traumatic encephalopathy inflammation tumor necrosis factor α interleukin 1 microglia astrocytes synaptic physiology N-methyl-D-aspartic acid

The herbal compound geniposide rescues formaldehyde-induced apoptosis in N2a neuroblastoma cells

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Science China(Life Sciences) 2014年第4期57卷 412-421,1-3页

作者： CHEN JinYan SUN MengRu WANG XingHua LU Jing WEI Yan TAN Yan LIU Ying GTZ Jürgen HE RongQiao HUA Qian Beijing University of Chinese Medicine Clem Jones Centre for Ageing dementia Research Queensland Brain Institute The University of QueenslandBrisbane Institute of Biophysics Chinese Academy of Sciences

The herbal medicine Tong Luo Jiu Nao （TLJN） contains geniposide （GP） and ginsenoside Rgl at a molar ratio of i0：1. Rgl is the major component of another herbal medicine, panax notoginseng saponin （PNS）. TLJN has been shown to strengthen brain function in humans, and in animals it improves learning and memory. We have previously shown that TLJN reduces amyloi- dogenic processing in Alzheimer＇s disease （AD） mouse models. Together this suggests TLJN may be a potential treatment for patients with dementia. Because chronic damage of the central nervous system by formaldehyde （FA） has been presented as a risk factor for age-associated cognitive dysfunction, in the present study we investigated the protective effect of both TLJN and GP in neuron-like cells exposed to FA. FA-exposed murine N2a neuroblastoma cells were incubated with TLJN, its main in- gredient GP, as well as PNS, to measure cell viability and morphology, the rate of apoptosis and expression of genes encoding Akt, FOXO3, Bcl2 and p53. The CCK-8 assay, cytoskeletal staining and flow cytometry were used to test cell viability, mor- phology and apoptosis, respectively. Fluorescent quantitative real-time PCR （qRT-PCR） was used to monitor changes in gene expression, and HPLC to determine the rate of FA clearance. Treatment of N2a cells with 0.09 mmol L-1 FA for 24 h signifi- cantly reduced cell viability, changed cell morphology and promoted apoptosis. Both TLJN and GP conferred neuroprotection to FA-treated N2a cells, whereas PNS, which had to be used at lower concentrations because of its toxicity, did not. Our data demonstrate that TLJN can rescue neuronal damage caused by FA and that its main ingredient, GP, has a major role in this ef- ficacy. This presents purified GP as a drug or lead compound for the treatment of AD.

关键词： Alzheimer's disease apoptosis formaldehyde geniposide neuroprotection panax notoginseng saponin Tong Luo Jiu Nao

Acute cerebral small vessel disease: Classification, mechanism, and therapeutic implications

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中华医学杂志(英文版) 2024年第21期137卷 2561页

作者： Yan Yuying Cheng Yajun Jiang Shuai Xu Mangmang Ye Chen Kwapong William Robert Tao Wendan Zhang Shuting Wardlaw Joanna M. Liu Ming Wu Bo Department of Neurology West China Hospital Sichuan University Chengdu Sichuan China Centre for Clinical brain Sciences UK Dementia Research Institute University of Edinburgh Edinburgh UK

[8,9] Perfusion imaging can be used to measure BBB integrity and microvasculature function, potentially providing early clues for clinical outcomes.[...]advanced diffusion and functional imaging can assess brain microstructure and function from a network and global perspective.[11] Retinal and choroidal structures assessed by optical coherence tomography/optical coherence tomography angiography have the potential to serve as surrogate markers of CSVD burden, brain volume, and optic tract shrinkage.[14] For hemorrhagic aCSVD, achieving a systolic blood pressure (SBP) below 140 mmHg within a few hours after stroke onset is safe and can improve functional outcomes, which is one of the critical management in hyperacute and acute stages.Funding This study was supported by grants from the National Natural Science Foundation of China (Nos. 82071320, 82371322, 82301661, and 82271328), 1·3·5 project for disciplines of excellence—Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2020HXFH012), China Postdoctoral Science Foundation (Nos. 2022M712249 and 2023T160447);

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