Daniela Lecca1, Yoo Jin Jung1,2, Michael T Scerba1, Inho Hwang3, Yu Kyung Kim3, Sun Kim3, Sydney Modrow4, David Tweedie1, Shih-Chang Hsueh1, Dong Liu1, Weiming Luo1, Elliot Glotfelty1,5, Yazhou Li1, Jia-Yi Wang6,7,8, Yu Luo9, Barry J Hoffer10, Dong Seok Kim3,11, Ross A McDevitt4, Nigel H Greig1. 1. Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, Maryland, USA. 2. Stanford Neurosciences Interdepartmental Program, Stanford University School of Medicine, Stanford, California, USA. 3. Aevis Bio, Inc., Daejeon, Republic of Korea. 4. Comparative Medicine Section, National Institute on Aging, Baltimore, Maryland, USA. 5. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. 6. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. 7. Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. 8. Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan. 9. Department of Molecular Genetics and Biochemistry, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA. 10. Department of Neurological Surgery, Case Western Reserve University Hospital, Cleveland, Ohio, USA. 11. AevisBio, Inc., Gaithersburg, Maryland, USA.
Abstract
OBJECTIVE: Evaluating the efficacy of 3,6'-dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline. BACKGROUND: Amyloid-β (Aβ) or tau-focused clinical trials have proved unsuccessful in mitigating AD-associated cognitive impairment. Identification of new drug targets is needed. Neuroinflammation is a therapeutic target in neurodegenerative disorders, and TNF-α a pivotal neuroinflammatory driver. NEW HYPOTHESIS: AD-associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aβ generation will define the role of neuroinflammation in AD progression. MAJOR CHALLENGES: Difficulty of TNF-α-lowering compounds reaching brain, and identification of a therapeutic-time window to preserve the beneficial role of neuroinflammatory processes. LINKAGE TO OTHER MAJOR THEORIES: Microglia/astroglia are heavily implicated in maintenance of synaptic plasticity/function in healthy brain and are disrupted by Aβ. Mitigation of chronic gliosis can restore synaptic homeostasis/cognitive function.
OBJECTIVE: Evaluating the efficacy of 3,6'-dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline. BACKGROUND: Amyloid-β (Aβ) or tau-focused clinical trials have proved unsuccessful in mitigating AD-associated cognitive impairment. Identification of new drug targets is needed. Neuroinflammation is a therapeutic target in neurodegenerative disorders, and TNF-α a pivotal neuroinflammatory driver. NEW HYPOTHESIS: AD-associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aβ generation will define the role of neuroinflammation in AD progression. MAJOR CHALLENGES: Difficulty of TNF-α-lowering compounds reaching brain, and identification of a therapeutic-time window to preserve the beneficial role of neuroinflammatory processes. LINKAGE TO OTHER MAJOR THEORIES: Microglia/astroglia are heavily implicated in maintenance of synaptic plasticity/function in healthy brain and are disrupted by Aβ. Mitigation of chronic gliosis can restore synaptic homeostasis/cognitive function.
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Authors: Holly Oakley; Sarah L Cole; Sreemathi Logan; Erika Maus; Pei Shao; Jeffery Craft; Angela Guillozet-Bongaarts; Masuo Ohno; John Disterhoft; Linda Van Eldik; Robert Berry; Robert Vassar Journal: J Neurosci Date: 2006-10-04 Impact factor: 6.167
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