scholarly journals Changes in the activity of lysosomal cysteine proteases of plasma mononuclear and polymorphonuclear blood leukocytes in Alzheimer’s disease

2020 ◽  
Vol 19 (3) ◽  
pp. 83-88
Author(s):  
M. G. Sorokina ◽  
M. A. Fomina ◽  
D. S. Petrov ◽  
N. V. Korotkova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cysteine Proteases ◽  
Blood Leukocytes ◽  
Lysosomal Cysteine Proteases

scholarly journals Diagnosing Alzheimer’s Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe

2021 ◽  
pp. 1-14
Author(s):  
Stefanie A.G. Black ◽  
Anastasiia A. Stepanchuk ◽  
George W. Templeton ◽  
Yda Hernandez ◽  
Tomoko Ota ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Blood Leukocytes ◽  
Peripheral Blood Mononuclear ◽  
The Brain

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

scholarly journals Calpain Dysregulation in Alzheimer’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Adriana Ferreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Marked Decrease ◽  
Senile Plaques ◽  
Cysteine Proteases ◽  
Axonal Guidance ◽  
Cell Functions ◽  
Multiple Cell ◽  
Axonal Guidance Growth ◽  
Differentiation And Proliferation

Alzheimer’s disease (AD) is characterized by the presence of senile plaques and neurofibrillary tangles in the neocortex and hippocampus of AD patients. In addition, a marked decrease in synaptic contacts has been detected in these affected brain areas. Due to its prevalence in the aging population, this disease has been the focus of numerous studies. The data obtained from those studies suggest that the mechanisms leading to the formation of the hallmark lesions of AD might be linked. One of such mechanisms seems to be the dysregulation of calcium homeostasis that results in the abnormal activation of calpains. Calpains are a family of Ca2+-dependent cysteine proteases that play a key role in multiple cell functions including cell development, differentiation and proliferation, axonal guidance, growth cone motility, and cell death, among others. In this paper, we briefly reviewed data on the structure of these proteases and their regulation under normal conditions. We also summarized data underscoring the participation of calpains in the neurodegenerative mechanisms associated with AD.

scholarly journals Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

2020 ◽  
Vol 21 (3) ◽  
pp. 1144
Author(s):  
Ariel Angel ◽  
Rotem Volkman ◽  
Tabitha Grace Royal ◽  
Daniel Offen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Cysteine Proteases ◽  
Knock Out ◽  
Model Of Alzheimer’S Disease ◽  
Caspase 6 ◽  
5Xfad Mice

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.

scholarly journals Design and Synthesis of Cysteine Proteases Inhibitors

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 86
Author(s):  
Florenci V. Gonzalez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chagas Disease ◽  
Therapeutic Targets ◽  
Cysteine Proteases ◽  
Sleeping Sickness ◽  
New Drugs ◽  
Tropical Diseases ◽  
Design And Synthesis

Cysteine proteases belonging to the papain superfamily have been recognized as interesting therapeutic targets for the search for new drugs against infectious tropical diseases such as malaria (falcipain), Chagas’ disease (curtain), leishmaniasis, and Sleeping sickness (rhodesian), and a number of human pathologies, including cancer, Alzheimer’s disease, and osteoporosis (cathepsins). [...]

scholarly journals Lysosomal processing of amyloid precursor protein to Aβ peptides: a distinct role for cathepsin S

1995 ◽  
Vol 311 (1) ◽  
pp. 299-305 ◽  
Author(s):  
J S Munger ◽  
C Haass ◽  
C A Lemere ◽  
G P Shi ◽  
W S F Wong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Cathepsin D ◽  
Cysteine Proteases ◽  
Precursor Protein ◽  
The Other ◽  
Cathepsin S ◽  
Potential Contribution ◽  
Lysosomal Compartment

To investigate the potential contribution of the lysosomal compartment in the processing of amyloid precursor protein (APP) to amyloid beta-peptides (A beta s), we stably overexpressed a series of lysosomal proteases (the cysteine proteases, cathepsins B, L and S, and the aspartic protease, cathepsin D) in a human kidney epithelial cell line (293) transfected to express high levels of beta APP. Preliminary experiments indicated that 293 cells endogenously synthesize cathepsins B, L and D, but not cathepsin S. A beta secretion was assessed by immunoprecipitation and ELISA and found to be increased approximately 2-fold following cathepsin S expression, but to be unchanged (cathepsins B, L) or decreased (cathepsin D) in the other double transfectants. E-64d, an inhibitor of lysosomal cysteine proteases, significantly reduced A beta secretion by the cathepsin S transfectants, but had no effect on cells expressing the other proteases. Radiosequencing of A beta secreted by cathepsin S-expressing cells revealed that a previously unreported variant beginning at Met -1 (relative to the most common A beta N-terminus, Asp -1) accounted for most of the increase in A beta secretion. Immunostaining of human brain sections revealed cathepsin S in cortical neurons and glia in samples of brain from patients with Alzheimer's disease. These results provide evidence in living cells for a pathway in which cathepsin S generates A beta from amyloidogenic fragments of beta APP in the endosomal/lysosomal compartment. This pathway appears to be inducible, distinct from a constitutive pathway used by 293 and other cells to generate A beta, and may be relevant to the pathogenesis of Alzheimer's disease.

scholarly journals Impaired Mitochondrial and Glycolytic Functions in Peripheral Blood Leukocytes of Alzheimer’s Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 120-120
Author(s):  
Ravindra Bharadwaj ◽  
Hayley Gibler ◽  
Sanjay Srivastava ◽  
Hena Tewari
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peripheral Blood ◽  
Normal Subjects ◽  
Blood Leukocytes ◽  
Blood Samples ◽  
Dementia Patients ◽  
Cellular Bioenergetics ◽  
Systemic Nature ◽  
Systemic Defect

Abstract Recent failures of the trials targeting amyloid to treat Alzheimer’s disease (AD) are prompting scientists to explore other pathological pathways. Brains of AD patients have been noted to have impaired mitochondrial function. It has not yet been determined if AD is caused by a systemic defect in cellular bioenergetics. To determine the cellular bioenergetics, we compared the Oxygen Consumption Rate (OCR – indicating oxygen dependent respiration) and Extra Cellular Acidification Rate (ECAR – indicating glycolytic function) in leukocytes of collected blood samples of Alzheimer’s and non-dementia patients. Methods: After IRB approval and consents, blood samples from each clinically diagnosed Alzheimer’s and age matched normal subjects were collected. Immediately after collection the blood samples were analyzed using Agilent Seahorse XFe/XF Analyzer as per protocol by manufacturer. Results: Impaired mitochondrial and glycolytic functions were noted in Alzheimer’s patients as compared to normal subjects. OCR was significantly lower in Alzheimer’s patients. A lower rate of respiration was noted both at basal as well as maximal respiration. Reduced spare respiration capacity was also noted in response to the stressors. Similarly reduced ECAR and reduced glycolytic reserve was also noted in Alzheimer’s patients, indicating impaired oxygen independent mitochondrial respiration. Discussion: This pilot study demonstrates that there is an impaired mitochondrial and glycolytic function in the peripheral blood cells. This indicates towards a systemic nature of the disease and a potential future bio-marker. Further studies should be planned in this direction.

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