The Potential Role of Ferroptosis in Alzheimer’s Disease

2021 ◽  
Vol 80 (3) ◽  
pp. 907-925
Author(s):  
Guimei Zhang ◽  
Yaru Zhang ◽  
Yanxin Shen ◽  
Yongchun Wang ◽  
Meng Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Iron Metabolism ◽  
Apoptotic Cell ◽  
Potential Interaction ◽  
Underlying Mechanisms ◽  
And Oxidative Stress

Alzheimer’s disease (AD) is the most prevalent cause of dementia, accounting for approximately 60%–80%of all cases. Although much effort has been made over the years, the precise mechanism of AD has not been completely elucidated. Recently, great attention has shifted to the roles of iron metabolism, lipid peroxidation, and oxidative stress in AD pathogenesis. We also note that these pathological events are the vital regulators of a novel regulatory cell death, termed ferroptosis—an iron-dependent, oxidative, non-apoptotic cell death. Ferroptosis differs from apoptosis, necrosis, and autophagy with respect to morphology, biochemistry, and genetics. Mounting evidence suggests that ferroptosis may be involved in neurological disorders, including AD. Here, we review the underlying mechanisms of ferroptosis; discuss the potential interaction between AD and ferroptosis in terms of iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 axis; and describe some associated studies that have explored the implication of ferroptosis in AD.

scholarly journals STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry

2018 ◽  
Vol 96 (10) ◽  
pp. 1061-1079 ◽  
Author(s):  
Carlos Pascual-Caro ◽  
Maria Berrocal ◽  
Aida M. Lopez-Guerrero ◽  
Alberto Alvarez-Barrientos ◽  
Eulalia Pozo-Guisado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Protein Expression ◽  
Transmembrane Domain ◽  
Neuroblastoma Cell ◽  
Disease Patient ◽  
List Type

Abstract STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. Key messages STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

scholarly journals Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease

2021 ◽  
Author(s):  
Roland Friedel ◽  
Yong Huang ◽  
Minghui Wang ◽  
Shalaka Wahane ◽  
Mitzy Ríos de Anda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Plaque ◽  
Reactive Astrocytes ◽  
Glial Activation ◽  
Plaque Burden ◽  
Aβ Amyloid ◽  
Underlying Mechanisms

Abstract Communication between glial cells has a profound effect on the pathophysiology of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Here, we reveal a role of reactive astrocytes in enforcing cell distancing in the glial nets surrounding amyloid plaques, which restricts microglial coverage of Aβ, a prerequisite to detect and engulf amyloid deposits. This process is mediated through guidance receptor Plexin-B1, which we identified as a key network regulator of late-onset AD. We show that Plexin-B1 is robustly upregulated in plaque-associated astrocytes in a corona-like pattern, and its expression levels correlate with plaque burden and disease severity in AD patients. In APP/PS1 mice, an amyloidogenic model of AD, removing Plexin-B1 led to smaller peri-plaque glial nets with relaxed cell distancing and enhanced glial coverage of Aβ plaques, as well as transcriptional changes in both reactive astrocytes and disease-associated microglia that are linked to glial activation and amyloid clearance. Furthermore, amyloid plaque burden was lowered, together with a shift towards dense-core plaques and reduced neuritic dystrophy. Our data thus support a role of Plexin-B1 in controlling glial net structure by imposing cell distancing, leading to poor glial coverage of Aβ, reduced amyloid clearance and compaction. Relaxing cell distancing by targeting guidance receptors may present an alternative strategy to alleviate neuroinflammation in AD by improving glial coverage of Aβ amyloid and plaque compaction.

P3-225: Role of presenilin-dependent gamma-secretase activity in the control of P53-mediated cell death in Alzheimer's disease

2006 ◽  
Vol 2 ◽  
pp. S441-S442
Author(s):  
Cristine Alves da Costa ◽  
Claire Sunyach ◽  
Raphaelle Pardossi-Piquard ◽  
Bruno Vincent ◽  
Jean Sevalle ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Gamma Secretase ◽  
Secretase Activity

Interleukin-17A in Alzheimer’s disease: recent advances and controversies

2021 ◽  
Vol 19 ◽  
Author(s):  
Xin-Zhu Yan ◽  
Laijun Lai ◽  
Qiang Ao ◽  
Xiao-hong Tian ◽  
Yan-hui Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Potential Role ◽  
Global Burden ◽  
Future Studies ◽  
The Past ◽  
Interleukin 17A ◽  
Underlying Mechanisms

: Alzheimer’s disease (AD) is a progressive neurodegenerative disease which mainly affects older adults. Although the global burden of AD is increasing year by year, the causes of AD remain largely unknown. Numerous basic and clinical studies have shown that interleukin-17A (IL-17A) may play a significant role in the pathogenesis of AD. A comprehensive assessment ofthe role of IL-17A in AD would benefit the diagnosis, understanding of etiology and treatment. However, over the past decade controversies remain regarding the expression level and role of IL-17A in AD. We have incorporated newly published researches and point out that IL-17A expression levels may vary along with the development of AD, exercising different roles at different stages of AD, although much more work remains to be done to support the potential role of IL-17A in AD-related pathology.Here, it is our intention to review the underlying mechanisms of IL-17A in AD and address the current controversies, in an effort to clarify the results of existing research and suggest future studies.

scholarly journals Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

2017 ◽  
Vol 214 (11) ◽  
pp. 3151-3169 ◽  
Author(s):  
Axel Montagne ◽  
Zhen Zhao ◽  
Berislav V. Zlokovic
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Neurodegenerative Process ◽  
Blood Brain ◽  
Underlying Mechanisms

The blood–brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer’s disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.

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