TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model DOI Creative Commons
Neha Basheer,

Muhammad Khalid Muhammadi,

Carlos L. Freites

и другие.

Frontiers in Aging Neuroscience, Год журнала: 2024, Номер 16

Опубликована: Окт. 21, 2024

Introduction Alzheimer’s disease (AD) is marked by the accumulation of fibrillary aggregates composed pathological tau protein. Although neuroinflammation frequently observed in conjunction with pathology, current preclinical evidence does not sufficiently establish a direct causal role tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced high dose lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary (NFT) pathology transgenic mouse model tauopathy that expresses human truncated 151-391/3R tau, an early feature sporadic AD. Methods We utilized subjected TLR4 stimulation via weekly intraperitoneal injections LPS over nine consecutive weeks. Neurofibrillary formation, microglial activation, and hyperphosphorylation brainstem hippocampus were assessed through immunohistochemistry, immunofluorescence, detailed morphometric analysis microglia. Results Chronic treatment led significant increase number Iba-1 + microglia LPS-treated group compared sham ( p < 0.0001). Notably, there was 1.5- 1.7-fold per tangle-bearing neuron group. These exhibited reactive yet exhausted phenotype, characterized reduction cell area 0.0001) without changes other parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive no decrease formation brainstem, where predominantly develops this model. Discussion findings suggest tau-transgenic mice results activation but influence underscores complexity relationship between indicating additional mechanisms may be required for directly contribute

Язык: Английский

Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases DOI
Ralph A. Nixon, David C. Rubinsztein

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(11), С. 926 - 946

Опубликована: Авг. 6, 2024

Язык: Английский

Процитировано

59
Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia DOI Open Access
Federica Pilotto,

Deepika M. Chellapandi,

Hélène Puccio

и другие.

Trends in Molecular Medicine, Год журнала: 2024, Номер 30(2), С. 117 - 125

Опубликована: Янв. 24, 2024

Язык: Английский

Процитировано

31
The hormesis principle of neuroplasticity and neuroprotection DOI Creative Commons
Mark P. Mattson, Rehana K. Leak

Cell Metabolism, Год журнала: 2024, Номер 36(2), С. 315 - 337

Опубликована: Янв. 10, 2024

Язык: Английский

Процитировано

19
Updates in Alzheimer's disease: from basic research to diagnosis and therapies DOI Creative Commons

Enjie Liu,

Yao Zhang,

Jian–Zhi Wang

и другие.

Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Сен. 4, 2024

Язык: Английский

Процитировано

17
Astrocytes in selective vulnerability to neurodegenerative disease DOI Creative Commons
Till S. Zimmer, Adam L. Orr, Anna G. Orr

и другие.

Trends in Neurosciences, Год журнала: 2024, Номер 47(4), С. 289 - 302

Опубликована: Март 22, 2024

Selective vulnerability of specific brain regions and cell populations is a hallmark neurodegenerative disorders. Mechanisms selective involve neuronal heterogeneity, functional specializations, differential sensitivities to stressors pathogenic factors. In this review we discuss the growing body literature suggesting that, like neurons, astrocytes are heterogeneous specialized, respond integrate diverse inputs, induce effects on function. disease, undergo specific, context-dependent changes that promote different trajectories outcomes. We propose contribute through maladaptive transitions context-divergent phenotypes impair functions. Further studies multifaceted roles in disease may provide new therapeutic approaches enhance resilience against

Язык: Английский

Процитировано

16
The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease DOI Creative Commons
Sriram Balusu, Bart De Strooper

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Июнь 1, 2024

Abstract Although apoptosis, pyroptosis, and ferroptosis have been implicated in AD, none fully explains the extensive neuronal loss observed AD brains. Recent evidence shows that necroptosis is abundant closely linked to appearance of Tau pathology, markers accumulate granulovacuolar neurodegeneration vesicles (GVD). We review here neuron-specific activation mediated neuronal-necroptosis pathway, potential AD-relevant triggers upstream this interaction necrosome with endo-lysosomal possibly providing links pathology. In addition, we underscore therapeutic inhibiting neurodegenerative diseases such as presents a novel avenue for drug development targeting preserve cognitive abilities. Such an approach seems particularly relevant when combined amyloid-lowering drugs.

Язык: Английский

Процитировано

11
Lecanemab‐Associated Amyloid‐β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease DOI Creative Commons
Moeko Noguchi‐Shinohara,

Kazuyoshi Shuta,

Hidetomo Murakami

и другие.

Annals of Neurology, Год журнала: 2025, Номер 97(5), С. 993 - 1006

Опубликована: Янв. 6, 2025

Objective The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted less decline on measures of cognition function than placebo. Herein, we aimed to characterize amyloid‐β (Aβ) protofibril (PF) captured by human cerebrospinal fluid (CSF) from living participants with different stages AD, which enable an enhanced understanding the dynamic changes lecanemab‐associated Aβ‐PF (Lec‐PF) vivo. Methods We newly developed a unique highly sensitive immunoassay method using selectively captures Lec‐PF. CSF level Lec‐PF, Aβ42, Aβ40, p‐tau181, p‐tau 217, total tau, neurogranin were measured Japanese (n = 163). this study consisted 48 cognitively unimpaired Aβ‐negative (CU–), 8 impaired diagnosed as suspected non‐Alzheimer's pathophysiology, 9 Aβ‐positive (CU+), 34 mild cognitive impairment (MCI+), 64 dementia (AD+). Results Lec‐PF levels significantly increased groups MCI+ AD+ compared CU– group. Notably, modest correlation plaque‐associated biomarkers stronger neurodegeneration biomarkers, such tau neurogranin, suggesting proximally reflect well amount senile plaques. Interpretation This is first report describing species supporting correlated may explain mechanism clinical effect lecanemab. ANN NEUROL 2025;97:993–1006

Язык: Английский

Процитировано

1
Proteins linking APOE ɛ4 with Alzheimer's disease DOI Creative Commons
Shahram Oveisgharan, Lei Yu, Kátia de Paiva Lopes

и другие.

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(7), С. 4499 - 4511

Опубликована: Июнь 10, 2024

Abstract INTRODUCTION The ɛ4 allele of the apolipoprotein E gene ( APOE ɛ4) is strongest genetic risk factor for Alzheimer's disease (AD), but mechanisms connecting to AD are not clear. METHODS Participants n = 596) were from two clinical‐pathological studies. Tissues dorsolateral prefrontal cortex examined identify 8425 proteins. Post mortem pathological assessment used immunohistochemistry obtain amyloid beta (Aβ) load and tau tangle density. RESULTS In separate models, was associated with 18 proteins, which Aβ tangles. Examining proteins in a single model identified Netrin‐1 secreted frizzled‐related protein 1 (SFRP1) as linking largest effect sizes testican‐3 DISCUSSION We Netrin‐1, SFRP1, most promising that link Highlights Of extracted cortex, related ɛ4. also tau. more than other variants. Aβ.

Язык: Английский

Процитировано

7
CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly DOI Creative Commons
Francis Shue, Launia J. White, Rachel Hendrix

и другие.

Science Advances, Год журнала: 2024, Номер 10(14)

Опубликована: Апрель 3, 2024

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, sex affect inflammatory molecules AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (

Язык: Английский

Процитировано

6
White matter aging and its impact on brain function DOI Creative Commons
Janos Groh, Mikael Simons

Neuron, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Aging has a detrimental impact on white matter, resulting in reduced volume, compromised structural integrity of myelinated axons, and an increase matter hyperintensities. These changes are closely linked to cognitive decline neurological disabilities. The deterioration myelin its diminished ability regenerate as we age further contribute the progression neurodegenerative disorders. Understanding these is crucial for devising effective disease prevention strategies. Here, will discuss alterations that occur with aging examine cellular molecular mechanisms driving aging-related transformations. We highlight how progressive disruption may initiate self-perpetuating cycle inflammation neural damage.

Язык: Английский

Процитировано

4