scholarly journals Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons

Brain ◽  
2006 ◽  
Vol 129 (11) ◽  
pp. 3020-3034 ◽  
Author(s):  
J. Padmanabhan ◽  
M. Levy ◽  
D. W. Dickson ◽  
H. Potter
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Phosphorylation ◽  
Inflammatory Protein

scholarly journals Alpha 1-Antichymotrypsin, an Inflammatory Protein Overexpressed in the Brains of Patients with Alzheimer’s Disease, Induces Tau Hyperphosphorylation through c-Jun N-Terminal Kinase Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Ethika Tyagi ◽  
Tina Fiorelli ◽  
Michelle Norden ◽  
Jaya Padmanabhan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Interleukin 1 ◽  
Tau Phosphorylation ◽  
Primary Neurons ◽  
Tau Hyperphosphorylation ◽  
Kinase Activation ◽  
Inflammatory Protein ◽  
Jnk Inhibitors ◽  
Inflammatory Proteins

The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer’s disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1β(IL-1β) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1βinjection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD.

scholarly journals “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yuxing Xia ◽  
Stefan Prokop ◽  
Benoit I. Giasson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Kinase Inhibitors ◽  
Tau Phosphorylation ◽  
Phosphorylated Tau ◽  
Clinical Biomarkers ◽  
Early Results ◽  
Recent Developments ◽  
Tau Aggregation

AbstractPhosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau  could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

Mediators of tau phosphorylation in the pathogenesis of Alzheimer’s disease

2009 ◽  
Vol 9 (11) ◽  
pp. 1647-1666 ◽  
Author(s):  
Diane P Hanger ◽  
Anjan Seereeram ◽  
Wendy Noble
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Phosphorylation

scholarly journals HERPESVIRUS INFECTIONS AND CLINICAL-IMMUNOLOGIC INTERACTIONS IN PATIENTS WITH EARLY-ONSET ALZHEIMER’S DISEASE AND LATE-ONSET ALZHEIMER’S DISEASE

2021 ◽  
Vol 23 (4) ◽  
pp. 805-812
Author(s):  
I. K. Malashenkova ◽  
D. P. Ogurtsov ◽  
S. A. Krynskiy ◽  
N. A. Khailov ◽  
N. D. Selezneva ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Viral Load ◽  
Early Onset ◽  
Late Onset ◽  
Adaptive Immune Response ◽  
Subsequent Development ◽  
Chronic Infections ◽  
Immune Parameters ◽  
Inflammatory Protein

Alzheimer’s disease (AD) is currently the most common cause of dementia. A significant role in the pathogenesis of AD belongs to the activation of the mechanisms of neuroinflammation. There is a hypothesis that chronic infections may play a role in the maintenance of the inflammatory response in AD. The aim of this work was to study the detection rate and DNA level of herpesviruses, as well as their possible relationship with the level of the key cytokines and with clinical parameters of AD in patients with early and late onset. 30 patients with AD and 33 healthy volunteers were enrolled. The quantitative determination of DNA of CMV, EBV, HHV-6, HHV-7 was carried out by PCR. The level of cytokines and soluble IL-1β antagonist (IL-1ra) in the blood was determined by ELISA. Herpesvirus infection with increased viral load was determined if at least one of the criteria was present: 1) DNA level of EBV and/or HHV-6 > 10,000 copies/ml in saliva; 2) presence of DNA of at least one of the EBV, HHV-6, HHV-7 viruses in the blood. In the subgroup of patients with early onset and increased viral load, there was a higher increase in the levels of a number of cytokines: proinflammatory IL-8 and IL-12, a Th2-cytokine IL-4, a cytokine of the adaptive immune response IL-2. However, the level of the anti-inflammatory protein IL-1ra was lower than in the controls. These changes may indicate a dysregulation of the antiviral response, with a predominance of activation of systemic inflammation and Th2-mediated reactions. Also, in early onset AD the increased viral load was associated with lower scores on Boston naming test. The results indicate that in studies of AD mechanisms and in the search for prognostic markers of the disease, it is important to take into account the heterogeneity of AD in terms of genetic predisposition factors, risk factors, immune parameters and clinical data. Such approach is necessary for the subsequent development of personalized approaches to the prevention and treatment of AD. 

Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease

2001 ◽  
Vol 103 (1) ◽  
pp. 26-35 ◽  
Author(s):  
Jean C. Augustinack ◽  
Anja Schneider ◽  
Eva-Maria Mandelkow ◽  
Bradley T. Hyman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Phosphorylation ◽  
Phosphorylation Sites

Genipin Attenuates Tau Phosphorylation and Aβ Levels in Cellular Models of Alzheimer's Disease

2021 ◽  
Author(s):  
Meiting Li ◽  
Nan Cai ◽  
Liang Gu ◽  
Lijun Yao ◽  
Decheng Bi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Tau Phosphorylation ◽  
Brain Disorder ◽  
Cellular Models ◽  
Aβ Generation ◽  
Aβ Production

Abstract Alzheimer’s disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules are considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

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