Faulty regulation of tau phosphorylation by the reelin signal transduction pathway is a potential mechanism of pathogenesis and therapeutic target in Alzheimer's disease

2006 ◽  
Vol 16 (8) ◽  
pp. 547-551 ◽  
Author(s):  
Stephen I. Deutsch ◽  
Richard B. Rosse ◽  
Lynn H. Deutsch
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signal Transduction ◽  
Therapeutic Target ◽  
Signal Transduction Pathway ◽  
Tau Phosphorylation ◽  
Transduction Pathway ◽  
Potential Mechanism

The Phosphoinositide Signal Transduction Pathway in the Pathogenesis of Alzheimer’s Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 355-362 ◽  
Author(s):  
Vincenza Rita Lo Vasco
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signal Transduction ◽  
Membrane Trafficking ◽  
Hormone Secretion ◽  
Signal Transduction Pathway ◽  
Brain Morphology ◽  
Signal Transduction Pathways ◽  
Transduction Pathway ◽  
Cell Functions

Background: During aging and in age-associated disorders, such as Alzheimer's Disease (AD), learning abilities decline. Probably, disturbances in signal transduction in brain cells underlie the cognitive decline. The phosphorylation/dephosphorylation imbalance occurring in degenerating neurons was recently related to abnormal activity of one or more signal transduction pathways. AD is known to be associated with altered neuronal Ca<sup>2+</sup> homeostasis, as Ca<sup>2+</sup> accumulates in affected neurons leading to functional impairment. It is becoming more and more evident the involvement of signal transduction pathways acting upon Ca<sup>2+</sup> metabolism and phosphorylation regulation of proteins. A growing interest raised around the role of signal transduction systems in a number of human diseases including neurodegenerative diseases, with special regard to the systems related to the phosphoinositide (PI) pathway and AD. The PI signal transduction pathway plays a crucial role, being involved in a variety of cell functions, such as hormone secretion, neurotransmitter signal transduction, cell growth, membrane trafficking, ion channel activity, cytoskeleton regulation, cell cycle control, apoptosis, cell and tissue polarity, and contributes to regulate the Ca<sup>2+</sup> levels in the nervous tissue. Conclusion: A number of observations indicated that PI-specific phospholipase C (PLC) enzymes might be involved in the alteration of neurotransmission. To understand the role and the timing of action of the signalling pathways recruited during the brain morphology changes during the AD progression might help to elucidate the aetiopathogenesis of the disease, paving the way to prognosis refinement and/or novel molecular therapeutic strategies.

Lyn Is an Important Component of the Signal Transduction Pathway Specific to FLT3/ITD and Can Be a Therapeutic Target in the Treatment of AML with FLT3/ITD.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1908-1908
Author(s):  
Fumihiko Hayakawa ◽  
Mitsunori Okamoto ◽  
Akihiro Abe ◽  
Hitoshi Kiyoi ◽  
Tomoki Naoe
Keyword(s):  
Signal Transduction ◽  
Cell Growth ◽  
Therapeutic Target ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Signal Transduction Pathway ◽  
Sh2 Domain ◽  
Transduction Pathway ◽  
Mice Model ◽  
Juxtamembrane Domain

Abstract Fms-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells. An internal tandem duplication (ITD) of the FLT3 juxtamembrane domain (FLT3/ITD) is the most frequent mutation in human adult acute myeloid leukemia (AML). Being transfected into IL-3 dependent cell line, 32D, FLT3/ITD causes constitutive activation of FLT3 itself and its downstream signal components, which leads to IL-3 independent cell growth. In particular, STAT5 activation is thought to be a key signaling event since it is induced only by FLT3/ITD not by wild type FLT3. However the signal component which mediates FLT3/ITD to STAT5 is yet to be clarified. In the present study, we showed the mutant- specific association of FLT3/ITD with Lyn, which led to the phosphorylation of Lyn in vivo. We also demonstrated that Lyn directly bound to FLT3 through its SH2 domain in vitro and that the association depended on tyrosyl-phosphorylation at juxtamembrane domain of FLT3. We revealed the critical role of Lyn for STAT5 activation and the autonomous cell growth in FLT3/ITD transfectant of 32D by using anti-Lyn siRNA and the Src family kinase inhibitor PP2. More importantly, we demonstrated successful treatment of FLT3/ITD induced tumors with PP2 in the mice model. These results demonstrate that Lyn is a critical component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD.

scholarly journals Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

2008 ◽  
Vol 55 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Kunihiro TSUCHIDA ◽  
Masashi NAKATANI ◽  
Akiyoshi UEZUMI ◽  
Tatsuya MURAKAMI ◽  
Xueling CUI
Keyword(s):  
Signal Transduction ◽  
Therapeutic Target ◽  
Musculoskeletal Diseases ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Activin Receptors

scholarly journals Focused ultrasound and Alzheimer’s disease A systematic review

2018 ◽  
Vol 12 (4) ◽  
pp. 353-359 ◽  
Author(s):  
Rodrigo Marmo da Costa e Souza ◽  
Inaê Carolline Silveira da Silva ◽  
Anna Beatriz Temoteo Delgado ◽  
Pedro Hugo Vieira da Silva ◽  
Victor Ribeiro Xavier Costa
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Effective Treatment ◽  
Cognitive Performance ◽  
Therapeutic Target ◽  
Focused Ultrasound ◽  
Tau Phosphorylation ◽  
Promising Therapeutic Target ◽  
Preclinical Trials

ABSTRACT Alzheimer’s disease (AD) affects millions of people, however, there is still no effective treatment. The use of focused ultrasound with microbubbles (FUS-MB) for the opening of the blood-brain barrier has been recently studied and may become a promising therapeutic target. Objective: To discuss the use of FUS-MB for the treatment of AD and to present some of the techniques used. Methods: A systematic review was performed of MEDLINE/PubMed and Biblioteca Virtual em Saúde (BVS) services, using the keywords: focused ultrasound, Alzheimer, amyloid-b. Original articles were included in the study; studies that did not focus on Alzheimer’s treatment were excluded. Results: Fifteen original studies were selected. Preclinical trials were able to reduce amyloid-b plaques and tau phosphorylation, improving cognitive performance in AD animals. Conclusion: The results are very promising, but the therapy still requires maturation. Further studies are needed to systematize all the techniques used and their effects in order to enable use in humans.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

Sign in / Sign up

Export Citation Format

Share Document