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Tuesday, November 1, 2016
Highlighted Article: DNA Double Strand Breaks: A Common Theme in Neurodegenerative Diseases
DNA Double Strand Breaks: A Common Theme in Neurodegenerative Diseases
Author(s):
Daniela Merlo, Cristiana Mollinari, Mauro Racaniello, Enrico Garaci and Alessio Cardinale Pages 1208 - 1218 ( 11 )
Abstract:
Accumulation of DNA damage and impairment of DNA repair systems are involved in the pathogenesis of different neurodegenerative diseases. Whenever DNA damage is too extensive, the DNA damage response pathway provides for triggering cellular senescence and/or apoptosis. However, whether the increased level of DNA damage in neurodegenerative disorders is a cause rather than the consequence of neurodegenerative events remains to be established. Among possible DNA lesions, DNA double strand breaks (DSBs) are rare events, nevertheless they are the most lethal form of DNA damage. In neurons, DSBs are particularly deleterious because of their reduced DNA repair capability as compared to proliferating cells.
Here, we provide a description of DSB repair systems and describe human studies showing the presence of several types of DNA lesions in three major neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). Then, we analyze the role of DSB accumulation and deficiency of DSB repair systems in neurodegeneration by examining studies on animal models of neurodegenerative diseases.
Keywords:
Alzheimer's disease, DNA damage, DNA repair, DNA double strand breaks, Huntington's disease, neurodegenerative diseases, Parkinson's disease.
Affiliation:
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
For More Information Please Visit Our Website Current Alzheimer Research
Monday, October 24, 2016
Most Cited Article: Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction
Identification of
Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction
Author(s):
Koteswara R. Valaasani, Qinru Sun, Gang Hu,
Jianping Li, Fang Du, Yaopeng Guo, Emily A. Carlson, Xueqi Gan and Shirley S.
YanPages 128-136 (9)
Abstract:
Amyloid beta (Aβ ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ )-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer’s disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished A β-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.
Keywords:
ABAD inhibitors, adenosine-5'-triphosphate,
amyloid beta, benzothiazole amino phosphonates, cytochrome c oxidase,
mitochondrial dysfunction.
Affiliation:
2099 Constant Avenue, University of Kansas,
Lawrence, KS 66047, USA.
For More Information Please Visit Our Website Current Alzheimer Research
Tuesday, October 18, 2016
The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease
Article Details
The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau
Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease
Author(s):
Marco Magistri, Dmitry Velmeshev, Madina
Makhmutova, Prutha Patel, Gregory C. Sartor, Claude-Henry Volmar, Claes
Wahlestedt and Mohammad Ali FaghihiPages 985-995 (11)
Abstract:
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.
Keywords:
Alzheimer’s disease, astrocytes, inflammation,
microglia, neuroinflammation, bromodomain, JQ1, splenomegaly.
Affiliation:
Center for Therapeutic Innovation & Department
of Psychiatry and Behavioral Sciences, University of Miami Miller School of
Medicine, 1501 NW 10th Ave, BRB 508, Miami, FL 33136, USA.
For more information please visit out website Current
Alzheimer Research