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Review
. 2024 Jun 19:17:1424561.
doi: 10.3389/fnmol.2024.1424561. eCollection 2024.

The role of Foxo3a in neuron-mediated cognitive impairment

Qin-Qin Liu  1 , Gui-Hua Wu  1 , Xiao-Chun Wang  1 , Xiao-Wen Xiong  1 , Rui-Wang  1 , Bao-Le Yao  1
Affiliations
Review

The role of Foxo3a in neuron-mediated cognitive impairment

Qin-Qin Liu et al. Front Mol Neurosci. .

Abstract

Cognitive impairment (COI) is a prevalent complication across a spectrum of brain disorders, underpinned by intricate mechanisms yet to be fully elucidated. Neurons, the principal cell population of the nervous system, orchestrate cognitive processes and govern cognitive balance. Extensive inquiry has spotlighted the involvement of Foxo3a in COI. The regulatory cascade of Foxo3a transactivation implicates multiple downstream signaling pathways encompassing mitochondrial function, oxidative stress, autophagy, and apoptosis, collectively affecting neuronal activity. Notably, the expression and activity profile of neuronal Foxo3a are subject to modulation via various modalities, including methylation of promoter, phosphorylation and acetylation of protein. Furthermore, upstream pathways such as PI3K/AKT, the SIRT family, and diverse micro-RNAs intricately interface with Foxo3a, engendering alterations in neuronal function. Through several downstream routes, Foxo3a regulates neuronal dynamics, thereby modulating the onset or amelioration of COI in Alzheimer's disease, stroke, ischemic brain injury, Parkinson's disease, and traumatic brain injury. Foxo3a is a potential therapeutic cognitive target, and clinical drugs or multiple small molecules have been preliminarily shown to have cognitive-enhancing effects that indirectly affect Foxo3a. Particularly noteworthy are multiple randomized, controlled, placebo clinical trials illustrating the significant cognitive enhancement achievable through autophagy modulation. Here, we discussed the role of Foxo3a in neuron-mediated COI and common cognitively impaired diseases.

Keywords: Foxo3a; brain; cognitive impairment; cognitively impaired diseases; neurons.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Effects of common COI-inducing agents on neurons and cognition.
FIGURE 2
FIGURE 2
Schematic representation of the active structural domain of Foxo3a protein.
FIGURE 3
FIGURE 3
The effect of interaction of neuronal Foxo3a with other proteins on Foxo3a and neurons.
FIGURE 4
FIGURE 4
A mechanism of neuronal regulation through Foxo3a.
FIGURE 5
FIGURE 5
The dual role of Foxo3a in Alzheimer’s disease.
See this image and copyright information in PMC

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