Objective: To identify the association between tumor necrosis factor-α (TNF-α) signaling and mitochondrial unfolded protein responses (UPRmt) against ventricular expansion, we used the kaolin induced hydrocephalus mouse model (KIHMM).

Background: Ventriculomegaly induced by the abnormal flow of cerebrospinal fluid (CSF) leads to hydrocephalus, which is accompanied by gliosis and dysfunctional mitochondria.
However, the underlying mechanism of neuroinflammation and mitochondrial dysfunction by ventriculomegaly was not fully understood. Microenvironmental shear stress leads to UPRmt by inducing neuroinflammation.

Method: Eight weeks old male C57BL/6J mouse used, and Kaoline induced hydrocephalus model was made by stereotactic injection of 10 microL 25% kaolin in the cisterna magna. Ventricular size were measured after sacrificing contols (saline injection), 1 day after injection mouse, 3 days after injection mouse and 5 days after injection mouse. Open field test and horizontal grid test and neurological scoring were done for behavior analysis. Protein extraction and Western blotting using prefrontal cortex above the ventricle were done and, TNF-a, Iba-1, Lonp1, p65, Hsp60 were analyzed. Recruitment of microglia in the prefrontal cortex around the ventricular expansion area and secretion of TNF-α could aggravate the inflammatory response. Total qRT-PCR was done to the isolated fromt the BV-2 cell by using TRIzol reagent.

Results: Prominent dilated ventricle and motor behavior defects were observed in KIHMM. TNF-α in activated microglia and nuclear factor-κB (NF-κB) signaling activated in the prefrontal cortex above the expanded ventricles. Most interestingly, Hsp60 induction preceded TNF-α mediated neuroinflammation accompanied by an increase of UPRmt expression. By the silencing of Atf5 in activated microglia which is an upstream molecule of UPRmt, we identify the increased TNF-α expression and secretion.

Conclusion: We demonstrated that TNF-α mediated neuroinflammation mitigated by induction of UPRmt, it provides a new sight for the pathogenic target of hydrocephalus.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tnf-%ce%b1-mediated-neuroinflammation-associated-with-uprmt-in-kaolin-induced-hydrocephalus-mouse-model/