Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis

著者: Daniela Lecca, Yoo Jin Jung, Michael T. Scerba, Inho Hwang, Yu Kyung Kim, Sun Kim, Sydney Modrow, David Tweedie, Shih‐Chang Hsueh, Dong Liu, Weiming Luo, Elliot J. Glotfelty, Yazhou Li, Jia‐Yi Wang, Yu Luo, Barry J. Hoffer, Dong Seok Kim, Ross A. McDevitt, Nigel H. Greig - Alzheimer s & Dementia 2022 被引用: 211

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.