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Microglia modulation with 1070-nm light attenuates Aβ burden and cognitive impairment in Alzheimer's disease mouse model.

ABSTRACT: Photobiomodulation, by utilizing low-power light in the visible and near-infrared spectra to trigger biological responses in cells and tissues, has been considered as a possible therapeutic strategy for Alzheimer's disease (AD), while its specific mechanisms have remained elusive. Here, we demonstrate that cognitive and memory impairment in an AD mouse model can be ameliorated by 1070-nm light via reducing cerebral β-amyloid (Aβ) burden, the hallmark of AD. The glial cells, including microglia and astrocytes, play important roles in Aβ clearance. Our results show that 1070-nm light pulsed at 10 Hz triggers microglia rather than astrocyte responses in AD mice. The 1070-nm light-induced microglia responses with alteration in morphology and increased colocalization with Aβ are sufficient to reduce Aβ load in AD mice. Moreover, 1070-nm light pulsed at 10 Hz can reduce perivascular microglia and promote angiogenesis to further enhance Aβ clearance. Our study confirms the important roles of microglia and cerebral vessels in the use of 1070-nm light for the treatment of AD mice and provides a framework for developing a novel therapeutic approach for AD.

SUBMITTER: Tao L

PROVIDER: S-EPMC8423759 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here, we characterize the role of RAGE-TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both in vivo and in vitro models. In the hippocampus of 5xFAD mice microglial activation, cytokine secretion, and glial fibrillary acidic protein-enhanced expression are paralleled with increased TXNIP expression. TXNIP silencing or its pharmacological inhibition prevents neuroinflammation in those mice. TXNIP is also associated with RAGE and Aβ. In particular, RAGE-TXNIP axis is required for targeting Aβ in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Aβ transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Aβ toxicity. Furthermore, Aβ shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1β and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE-TXNIP axis inhibits Aβ-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Aβ to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1β and the pyroptosis pathway associated with GSDMD cleavage. Altogether these data shed new light on a novel mechanism of action of RAGE-TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD.

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Microglia modulation with 1070-nm light attenuates Aβ burden and cognitive impairment in Alzheimer's disease mouse model.

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