Alzheimer's disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer's disease is characterized by amyloid-beta and hyperphosphorylated tau, which are ...necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical benefits. Recent advances in fundamental research have indicated that neuroinflammation plays an important pathological role in AD. Damage- and pathogen-associated molecular patterns in the brain induce neuroinflammation and inflammasome activation, causing caspase-1-dependent glial and neuronal cell death. These waste products in the brain are eliminated by the glymphatic system via perivascular spaces, the blood-brain barrier, and the blood-cerebrospinal fluid barrier. Age-related vascular dysfunction is associated with an impairment of clearance and barrier functions, leading to neuroinflammation. The proteins involved in waste clearance in the brain and peripheral circulation may be potential biomarkers and drug targets in the early stages of cognitive impairment. This short review focuses on waste clearance dysfunction in AD pathobiology and discusses the improvement of waste clearance as an early intervention in prodromal AD and preclinical stages of dementia.
The spindle assembly checkpoint (SAC) monitors the attachment of microtubules to the kinetochore and inhibits anaphase when microtubule binding is incomplete. The SAC might also respond to tension; ...however, how cells can sense tension and whether its detection is important to satisfy the SAC remain controversial. We generated a HeLa cell line in which two components of the kinetochore, centromere protein A and Mis12, are labeled with green and red fluorophores, respectively. Live cell imaging of these cells reveals repetitive cycles of kinetochore extension and recoiling after biorientation. Under conditions in which kinetochore stretching is suppressed, cells fail to silence the SAC and enter anaphase after a delay, regardless of centromere stretching. Monitoring cyclin B levels as a readout for anaphase-promoting complex/cyclosome activity, we find that suppression of kinetochore stretching delays and decelerates cyclin B degradation. These observations suggest that the SAC monitors stretching of kinetochores rather than centromeres and that kinetochore stretching promotes silencing of the SAC signal.
Incorrect attachment of kinetochore microtubules is the leading cause of chromosome missegregation in cancers. The highly conserved chromosomal passenger complex (CPC), containing mitotic kinase ...Aurora B as a catalytic subunit, ensures faithful chromosome segregation through destabilizing incorrect microtubule attachments and promoting biorientation of chromosomes on the mitotic spindle. It is unknown whether CPC dysfunction affects chromosome segregation fidelity in cancers and, if so, how. Here, we show that heterochromatin protein 1 (HP1) is an essential CPC component required for full Aurora B activity. HP1 binding to the CPC becomes particularly important when Aurora B phosphorylates kinetochore targets to eliminate erroneous microtubule attachments. Remarkably, a reduced proportion of HP1 bound to CPC is widespread in cancers, which causes an impairment in Aurora B activity. These results indicate that HP1 is an essential modulator for CPC function and identify a molecular basis for chromosome segregation errors in cancer cells.
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•The HP1-binding capacity of the CPC is impaired in a wide range of cancer cells•HP1 binding to the CPC is required for full Aurora B activity•HP1-mediated full Aurora B activity ensures phosphorylation of kinetochore substrates•HP1 is an essential modulator of CPC preventing chromosome segregation errors
Improper kinetochore-microtubule attachments can cause chromosome missegregation, but are normally corrected through an Aurora B-dependent mechanism. Abe et al. find that the heterochromatin protein HP1 is required for full Aurora B activity and that HP1 association with the Aurora B complex is widely impaired in cancer cells with chromosomal instability.
Animal cells undergo rapid rounding during mitosis, ensuring proper chromosome segregation, during which an outward rounding force abruptly increases upon prometaphase entry and is maintained at a ...constant level during metaphase. Initial cortical tension is generated by the actomyosin system to which both myosin motors and actin network architecture contribute. However, how cortical tension is maintained and its physiological significance remain unknown. We demonstrate here that Cdk1-mediated phosphorylation of DIAPH1 stably maintains cortical tension after rounding and inactivates the spindle assembly checkpoint (SAC). Cdk1 phosphorylates DIAPH1, preventing profilin1 binding to maintain cortical tension. Mutation of DIAPH1 phosphorylation sites promotes cortical F-actin accumulation, increases cortical tension, and delays anaphase onset due to SAC activation. Measurement of the intra-kinetochore length suggests that Cdk1-mediated cortex relaxation is indispensable for kinetochore stretching. We thus uncovered a previously unknown mechanism by which Cdk1 coordinates cortical tension maintenance and SAC inactivation at anaphase onset.
The spindle-assembly checkpoint facilitates mitotic fidelity by delaying anaphase onset in response to microtubule vacancy at kinetochores. Following microtubule attachment, kinetochores receive ...microtubule-derived force, which causes kinetochores to undergo repetitive cycles of deformation; this phenomenon is referred to as kinetochore stretching. The nature of the forces and the relevance relating this deformation are not well understood. Here, we show that kinetochore stretching occurs within a framework of single end-on attached kinetochores, irrespective of microtubule poleward pulling force. An experimental method to conditionally interfere with the stretching allowed us to determine that kinetochore stretching comprises an essential process of checkpoint silencing by promoting PP1 phosphatase recruitment after the establishment of end-on attachments and removal of the majority of checkpoint-activating kinase Mps1 from kinetochores. Remarkably, we found that a lower frequency of kinetochore stretching largely correlates with a prolonged metaphase in cancer cell lines with chromosomal instability. Perturbation of kinetochore stretching and checkpoint silencing in chromosomally stable cells produced anaphase bridges, which can be alleviated by reducing chromosome-loaded cohesin. These observations indicate that kinetochore stretching-mediated checkpoint silencing provides an unanticipated etiology underlying chromosomal instability and underscores the importance of a rapid metaphase-to-anaphase transition in sustaining mitotic fidelity.
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•Intra-kinetochore stretching occurs within a framework of single kinetochores•Kinetochore stretching is an essential process for checkpoint silencing•Kinetochore stretching promotes PP1 recruitment at end-on attached kinetochores•Defective kinetochore stretching and checkpoint silencing are widespread in cancers
Uchida et al. show that kinetochore stretching, repetitive cycles of extension and recoiling, depends on the dynamic nature of microtubule tips, instead of the poleward-pulling force. By silencing the mitotic checkpoint, kinetochore stretching promotes a speedy transition from metaphase to anaphase and thereby fail-safe chromosome segregation.
During mitotic chromosome segregation, the protease separase severs cohesin between sister chromatids. A probe for separase activity has shown that separase undergoes abrupt activation shortly before ...anaphase onset, after being suppressed throughout metaphase; however, the relevance of this control remains unclear. Here, we report that separase activates precociously, with respect to anaphase onset, during prolonged metaphase in multiple types of cancer cell lines. The artificial extension of metaphase in chromosomally stable diploid cells leads to precocious activation and, subsequently, to chromosomal bridges in anaphase, which seems to be attributable to incomplete cohesin removal. Conversely, shortening back of a prolonged metaphase restores the activation of separase and ameliorates anaphase bridge formation. These observations suggest that retarded metaphase progression affects the separase activation profile and its enzymatic proficiency. Our findings provide an unanticipated etiology for chromosomal instability in cancers and underscore the relevance of swift mitotic transitions for fail-safe chromosome segregation.
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•Prolonged metaphase and separase deregulation are widespread among cancer cells•Delaying anaphase onset impairs activation profile and proficiency of separase•Shortening back of prolonged metaphase restores robust separase activation kinetics•Separase deregulation results in incomplete cohesin removal and anaphase bridges
Using a separase sensor, Shindo et al. show that separase is widely deregulated in cancer cells and that this deregulation is attributable to prolonged metaphase. A swift progression through metaphase to anaphase ensures characteristic sharp activation and proficiency of separase and therefore underlies faithful chromosome segregation.
Blood proteins can be used for biomarkers to monitor the progression of cognitive decline, even in the early stages of disease. In this study, we developed a liquid chromatography–tandem mass ...spectrometry (LC-MS/MS)-based blood test to identify plasma proteins that can be used to detect mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Using this system, we quantified plasma proteins using isotope-labeled synthetic peptides. A total of 192 patients, including 63 with AD, 71 with MCI, and 58 non-demented controls (NDCs), were analyzed. Multinomial regression and receiver operating characteristic (ROC) analyses were performed to identify specific combinations of plasma protein panels that could differentiate among NDCs, those with MCI, and those with AD. We identified eight plasma protein biomarker candidates that can be used to distinguish between MCI and AD. These biomarkers were associated with coagulation pathways, innate immunity, lipid metabolism, and nutrition. The clinical potential to differentiate cognitive impairment from NDC was assessed using area under the curve values from ROC analysis, which yielded values of 0.83 for males and 0.71 for females. This LC-MS-based plasma protein panel allows the pathophysiology of AD to be followed through detection of cognitive decline and disease progression markers.
PolyADP-ribosylation is a post-translational modification which is involved in various physiological processes including maintenance of genome stability through DNA repair, regulation of ...transcription, and development. This process is also involved in pathological events such as cell death. Here, we review the effect of polyADP-ribosylation in signal transduction pathways in
system. It is hoped that such an insight paves the way to develop therapeutics for human diseases.
Lifestyle habits after middle age significantly impact the maintenance of cognitive function in older adults. Nutritional intake is closely related to lifestyle habits; therefore, nutrition is a ...pivotal factor in the prevention of dementia in the preclinical stages. Matcha green tea powder (matcha), which contains epigallocatechin gallate, theanine, and caffeine, has beneficial effects on cognitive function and mood. We conducted a randomized, double-blind, placebo-controlled clinical study over 12 months to examine the effect of matcha on cognitive function and sleep quality. Ninety-nine participants, including 64 with subjective cognitive decline and 35 with mild cognitive impairment were randomized, with 49 receiving 2 g of matcha and 50 receiving a placebo daily. Participants were stratified based on two factors: age at baseline and APOE genotype. Changes in cognitive function and sleep quality were analyzed using a mixed-effects model. Matcha consumption led to significant improvements in social acuity score (difference; -1.39, 95% confidence interval; -2.78, 0.002) (P = 0.028) as evaluated by the perception of facial emotions in cognitive function. The primary outcomes, that is, Montreal Cognitive Assessment and Alzheimer's Disease Cooperative Study Activity of Daily Living scores, showed no significant changes with matcha intervention. Meanwhile, Pittsburgh Sleep Quality Index scores indicated a trend toward improvement with a difference of 0.86 (95% confidence interval; -0.002, 1.71) (P = 0.088) between the groups in changes from baseline to 12 months. The present study suggests regular consumption of matcha could improve emotional perception and sleep quality in older adults with mild cognitive decline. Given the widespread availability and cultural acceptance of matcha green tea, incorporating it into the daily routine may offer a simple yet effective strategy for cognitive enhancement and dementia prevention.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is characterized by immune system dysregulation after exposure to adjuvants, such as aluminum. Although cases of autoimmune thyroid ...diseases caused by ASIA have been reported, Graves' disease is one of the rarer diseases. There are some reports that vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause ASIA. Here, we describe a case of Graves' disease following SARS-CoV-2 vaccination and a review of the literature.
A 41-year-old woman was admitted to our hospital because of palpitations and fatigue. Two weeks after receiving the second SARS-CoV-2 vaccine (BNT162b2, Coronavirus Modified Uridine messenger RNA (mRNA) Vaccine, Pfizer), she developed fatigue and gradually worsened. On admission, she exhibited thyrotoxicosis (thyroid-stimulating hormone (TSH) < 0.01 mIU/L (0.08-0.54), free triiodothyronine (FT3) 33.2 pmol/L (3.8-6.3), and free thyroxine (FT4) 72.1 pmol/L (11.6-19.3)) and palpitations associated with atrial fibrillation. TSH receptor antibody (TRAb) was positive (TRAb 5.0 IU/L (< 2.0)), and
Tc scintigraphy showed diffuse uptake in the thyroid gland, suggesting that the thyrotoxicosis in this case was caused by Graves' disease. Thiamazole was prescribed to correct her condition, and soon after this treatment was initiated, her symptoms and thyroid hormone levels were significantly reduced.
This case report reinforces the potential correlation between ASIA affecting the thyroid and SARS-CoV-2 mRNA vaccines. The clinical course suggests that it is essential to consider the possibility of developing ASIA, such as Graves' disease, after exposure to the SARS-CoV-2 vaccine.
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