FOXG1 Improves Cognitive Function in Alzheimer's Disease by Promoting Endogenous Neurogenesis

 Will this prevent cognitive decline post stroke? Will your competent? doctor ENSURE SUCH RESEARCH GETS DONE? NO? So, you DON'T have a functioning stroke doctor, do you?

FOXG1 Improves Cognitive Function in Alzheimer's Disease by Promoting Endogenous Neurogenesis   

 Wen Pan  ^{1   2} , Long-Fei Xu  ² , Yu-Xin Wang  ² , Yi-Jie Wang  ² , Jia-Qing Wang  ² , Xin Qian  ² , Cheng-Zhi Zhou  ² , Hua Wang  ^{2   3} , Xiao-Hua Fan  ¹ , Jia Wang  ^{1   2   3}

Affiliations

• PMID: 40297942
• DOI: 10.1096/fj.202403299RR

Abstract

Strategies aimed at enhancing the capacity of neural stem cells (NSCs) to generate multipotential, proliferative, and migratory cell populations capable of efficient neuronal differentiation are crucial for structural repair following neurodegenerative damage. The role of Forkhead-box gene 1 (FOXG1) in pattern formation, cell proliferation, and specification has been established. However, its involvement in Alzheimer's disease (AD) remains largely unknown. Here, we investigated the association between Foxg1 gene variants and AD-like behavioral deficits, amyloid-β (Aβ) aggregate formation, as well as p21 expression. Furthermore, we explored whether targeting the FOXG1-regulated cell cycle contributes to the promotion of adult neurogenesis in the context of AD. In this study, we successfully induced overexpression of FOXG1 in the hippocampus of AD brains through adeno-associated virus-Foxg1 infusion. Activation of FOXG1 rescued spatial learning disabilities, short-term memory deficits, and sensorimotor gating impairments observed in AD transgenic animals. By inhibiting p21 WAF1/cyclin-dependent kinase interacting protein 1 (p21^cip1/waf1)-mediated cell cycle arrest, FOXG1 facilitates the activation and proliferation of NSCs. Additionally, the Foxg1 gene promotes an increase in precursor population size and enhances neuroblast differentiation. These combined effects on proliferation and differentiation lead to the generation of postmitotic neurons within the hippocampus in AD animals. Together, these findings demonstrate the importance of cooperation between FOXG1 and p21 for maintaining NSC self-renewal while facilitating neuronal lineage progression and contributing to endogenous neurogenesis during AD. Elevating levels of FOXG1 either pharmacologically or through alternative means could potentially serve as a therapeutic strategy for treating AD.

Keywords: Alzheimer's disease; FOXG1; adult neurogenesis; dentate gyrus; proliferation; β‐amyloid deposits.

© 2025 Federation of American Societies for Experimental Biology.   

Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival

Followup needed since nothing here can be directly used to help your recovery.
https://www.ncbi.nlm.nih.gov/pubmed/28484273

Swiatkowski P^1,2, Nikolaeva I^1,2, Kumar G¹, Zucco A^1,3, Akum BF¹, Patel MV^1,3, D'Arcangelo G¹, Firestein BL⁴.

Author information

Abstract

Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been implicated in the modulation and regulation of synaptic strength, activity, maturation, and axonal regeneration. The present study focuses on the physiology and survival of neurons following manipulation of Akt and several downstream targets, such as GSK3β, FOXO1, and mTORC1, prior to NMDA-induced injury. Our analysis reveals that exposure to sublethal levels of NMDA does not alter phosphorylation of Akt, S6, and GSK3β at two and twenty four hours following injury. Electrophysiological recordings show that NMDA-induced injury causes a significant decrease in spontaneous excitatory postsynaptic currents at both two and twenty four hours, and this phenotype can be prevented by inhibiting mTORC1 or mTORC1, but not Akt. Additionally, inhibition of mTORC1 or GSK3β promotes neuronal survival following NMDA-induced injury. Thus, NMDA-induced excitotoxicity involves a mechanism that requires the permissive activity of mTORC1 and GSK3β, demonstrating the importance of these kinases in the neuronal response to injury.

PMID:

28484273

PMCID:

PMC5431483

DOI:

10.1038/s41598-017-01826-w

Free PMC Article

Scientists discover a new gene linked to stroke

Not sure how useful this is for the cost of getting gene testing. 

Scientists discover a new gene linked to stroke

Researchers have discovered a gene linked to the risk of stroke that could lead to a better understanding of the devastating condition and how to prevent and treat it. The gene may also have a connection to dementia and depression, they say.
The scientists, from Boston University School of Medicine and the University of Bordeaux, in France, analyzed data on close to 85,000 people that had been collected between 1948 and 2013. About 4,300 had had a stroke.
Then they conducted a genome-wide analysis of common genetic variants associated with stroke, said study investigator Dr. Sudha Seshadri, a professor of neurology at Boston University School of Medicine.
"We looked at millions of markers in each person and said how do all the people who have stroke differ from all the people who don't have stroke in terms of these millions of markers," Seshadri told CBS News.
They identified seven known genes associated with stroke and also a new one, called FOXF2, linked to risk for all types of stroke. Specifically, it appeared to increase the risk of having a stroke due to small vessel disease in the brain, a common type of stroke.
Seshadri said that for every stroke that is diagnosed due to apparent symptoms, there are five silent strokes -- what she calls "covert strokes" -- which show up on MRI.
"More than 80 percent of these undiagnosed strokes are due to small vessel disease," she said.
No previous study has identified a gene for this common type of stroke, she pointed out; most have looked at genes linked with atherosclerosis, how platelets function and clotting processes in the blood -- risk factors for other types of strokes.
In addition to stroke, Seshadri said small vessel disease is associated with dementia risk, walking problems, depression and glaucoma, so learning about FOXF2 may help shed light on those conditions, too.
The study appears in the journal Lancet Neurology.

Key protein may affect risk of stroke

While this is good news, this just proves that no one seems to be willing to tackle solving the incredibly difficult problems in stroke. Leaders create strategies and tackle the difficult problems. They don't just sit back and continue down the failed status quo path. I need to quit getting mad about this before I blow an artery. But hell this is so fucking simple and obvious what needs to be done that I can't believe the thousands of highly educated stroke medical 'professionals' don't have enough brains to see the way forward. 

Oops, I'm not playing by the polite rules of Dale Carnegie,  'How to Win Friends and Influence People'. 

Telling your supposedly smart stroke medical 'professionals' they know nothing about stroke is a no-no even if it is true. 

Politeness will never solve anything in stroke. Yes, I'm a bomb thrower and proud of it. Someday a stroke 'leader' will try to ream me out for making them look bad by being truthful, I look forward to that day.

Key protein may affect risk of stroke

Studies on mice reveal that a special protein in the brain’s tiniest blood vessels may affect the risk of stroke. Peter Carlsson, professor in genetics at the University of Gothenburg, and his research team are publishing new research findings in the journal Developmental Cell about how the blood-brain barrier develops and what makes the capillaries in the brain different from small blood vessels in other organs.
The brain’s smallest blood vessels differ from those in other organs in that the capillary walls are much more compact. The nerve cells in the brain get the nutrients they need by molecules actively being transported from the blood, instead of passively leaking out from the blood vessels.
This blood-brain barrier is vital, because it enables strict control over the substances with which the brain’s nerve cells come into contact. It has a protective function that if it fails, increases the risk of stroke and other complications.
Special cell type essential to development
The smallest blood vessels, the capillaries, have a type of cell called pericytes. These are essential to the development of the blood-brain barrier. Pericytes are also found in other organs, and researchers have previously been unable to find out what gives the brain’s pericytes this unique ability.
The Gothenburg research team has found that the brain’s pericytes contain a protein, FoxF2, which is not present in the pericytes of other organs, and which coordinates the changes that make the blood vessels compact. FoxF2 is needed in order for the blood-brain barrier to form during foetal development.
“Mice that have too little or too much FoxF2 develop various types of defects in the brain’s blood vessels,” explains Peter Carlsson, professor at the University of Gothenburg’s Department of Chemistry and Molecular Biology.
One gene may play a critical role
In humans, researchers have noted that major changes in a region of chromosome 6 have been associated with an increased risk of stroke, but it has not been known which of the genes in the area are responsible for this risk.
“The FoxF2 gene is an extremely interesting candidate, as it is located right in the middle of this region, and research is under way now in collaboration with clinical geneticists to investigate the extent to which variations in the FoxF2 gene affect people’s risk of suffering a stroke,” says Peter Carlsson.
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http://www.gu.se/english/about_the_university/news-calendar/News_detail//key-protein-may-affect-risk-of-stroke.cid1310761

The Expression of FOXJ1 in Neurogenesis after Transient Focal Cerebral Ischemia

Your researcher should be able to match this up with all the other neurogenesis factors and translate that into a stroke protocol.

The Expression of FOXJ1 in Neurogenesis after Transient Focal Cerebral Ischemia

Authors

Yabo Huang¹, Zheng Xu¹, Jie Cao¹, Haibo Cao¹, Shiming Zhang¹

¹Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou, China

Abstract

Objective and Background: FOXJ1 is a member of the Forkhead/winged-helix (Fox) family of transcription factors, which is required for the differentiation of the cells acting as adult neural stem cells which participate in neurogenesis and give rise to neurons, astrocytes, oligodendrocytes. The expression pattern of FOXJ1 in the brain after cerebral ischemia has so far not been described. In the current study, we investigated the expression pattern of FOXJ1 in the rat brain after cerebral ischemia by animal model. Methods: We performed a middle cerebral artery occlusion (MCAO) model in adult rats and investigated the expression of FOXJ1 in the brain by Western blotting and immunochemistry; double immunofluorescence staining was used to analyze FOXJ1's co-expression with Ki67. Results: Western blot analysis showed that the expression of FOXJ1 was lower than normal and sham-operated brain after cerebral ischemia, but the level of FOXJ1 gradually increased from Day 1 to Day 14. Immuohistochemical staining suggested that the immunostaining of FOXJ1 deposited strongly in the ipsilateral and contralateral hemisphere in the cortical penumbra (CP). There was no FOXJ1 expression in the ischemic core (IC). The positive cells in the cortical penumbra might migrat to the ischemic core. In addition, double immunofluorescence staining revealed that FOXJ1 was co-expressed with mAP-2 and gFAP, and Ki67 had the colocalization with NeuN, GFAP, and FOXJ1. Conclusions: All our findings suggest that FOXJ1 plays an important role on neuronal production and neurogenesis in the adult brain after cerebral ischemia.