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

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 Glotfelty; Yazhou Li; Jia-Yi Wang; Yu Luo; Barry J Hoffer; Dong Seok Kim; Ross A McDevitt; Nigel H Greig

doi:10.1002/alz.12610

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

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 Glotfelty, Yazhou Li, Jia-Yi Wang, Yu Luo, Barry J Hoffer, Dong Seok Kim, Ross A McDevitt, Nigel H Greig

Research output: Contribution to journal › Article › peer-review

107 Citations (Scopus)

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.

Original language	English
Journal	Alzheimer's and Dementia
DOIs	https://doi.org/10.1002/alz.12610
Publication status	E-pub ahead of print - Mar 2 2022

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10.1002/alz.12610

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Lecca, D., Jung, Y. J., Scerba, M. T., Hwang, I., Kim, Y. K., Kim, S., Modrow, S., Tweedie, D., Hsueh, S.-C., Liu, D., Luo, W., Glotfelty, E., Li, Y., Wang, J.-Y., Luo, Y., Hoffer, B. J., Kim, D. S., McDevitt, R. A., & Greig, N. H. (2022). Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis. Alzheimer's and Dementia. Advance online publication. https://doi.org/10.1002/alz.12610

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title = "Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis",

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.",

author = "Daniela Lecca and Jung, {Yoo Jin} and Scerba, {Michael T} and Inho Hwang and Kim, {Yu Kyung} and Sun Kim and Sydney Modrow and David Tweedie and Shih-Chang Hsueh and Dong Liu and Weiming Luo and Elliot Glotfelty and Yazhou Li and Jia-Yi Wang and Yu Luo and Hoffer, {Barry J} and Kim, {Dong Seok} and McDevitt, {Ross A} and Greig, {Nigel H}",

note = "{\textcopyright} 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by US Government employees and their work is in the public domain in the USA.",

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doi = "10.1002/alz.12610",

language = "English",

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T1 - Role of chronic neuroinflammation in neuroplasticity and cognitive function

T2 - A hypothesis

AU - Lecca, Daniela

AU - Jung, Yoo Jin

AU - Scerba, Michael T

AU - Hwang, Inho

AU - Kim, Yu Kyung

AU - Kim, Sun

AU - Modrow, Sydney

AU - Tweedie, David

AU - Hsueh, Shih-Chang

AU - Liu, Dong

AU - Luo, Weiming

AU - Glotfelty, Elliot

AU - Li, Yazhou

AU - Wang, Jia-Yi

AU - Luo, Yu

AU - Hoffer, Barry J

AU - Kim, Dong Seok

AU - McDevitt, Ross A

AU - Greig, Nigel H

N1 - © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

PY - 2022/3/2

Y1 - 2022/3/2

N2 - 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.

AB - 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.

U2 - 10.1002/alz.12610

DO - 10.1002/alz.12610

M3 - Article

C2 - 35234334

SN - 1552-5260

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

ER -

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

Abstract

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