Title : Brain mitochondrial function and oxidative stress normalized after WWOX inhibition in a mouse model of type 2 diabetes
Abstract:
Type 2 diabetes (T2D) is a chronic metabolic disorder that significantly increases the risk of dementia, particularly Alzheimer’s disease (AD). It is of utmost importance to decipher the mechanisms underlying T2D-associated brain damage to facilitate the development of effective strategies capable of preventing or reducing dementia. It has been recently shown that WW domain-containing oxidoreductase 1 (WWOX) overexpression/overactivation plays a pivotal role in mitochondrial dysfunction and development of insulin resistance, features shared by T2D and AD. In this line, this study was aimed to 1) assess the involvement of WWOX in T2D-associated brain damage and 2) evaluate the therapeutic potential of Zfra1- 31 peptide, a specific inhibitor of WWOX.
High fat diet (HFD)-induced T2D mice treated or not with 2mM Zfra1-31 for 4weeks (4x; 1injection/week via tail vein) were used as experimental in vivo model. We performed a battery of behavioral and cognitive tests, and we evaluated glucose tolerance and insulin levels by ELISA and enzymatic methods. The levels of oxidative stress markers were evaluated by fluorometric techniques, and the function of brain cortical mitochondria was assessed using a XF24 Extracellular Flux Analyzer.
HFD induced a clear phenotype of T2D, as demonstrated by the increase in body weight and peripheral blood glucose levels and decreased glucose tolerance. T2D mice also showed increased levels of anxiety and impaired cognitive function. Mitochondria isolated from the brain cortex of T2D mice presented defects in the respiratory chain and phosphorylative system, decreased calcium buffering capacity and increased oxidative stress levels. Interestingly, T2D mice treated with Zfra1-31 showed an amelioration of blood glucose levels as well as of the anxiety-like behavior and memory impairment, compared to untreated mice Furthermore, Zfra1-31 improved brain mitochondrial respiratory chain, phosphorylation system and calcium buffering capacity and decreased oxidative stress levels. In conclusion, these observations demonstrate that HFD induces a phenotype of T2D associated to behavioral/cognitive and mitochondrial defects. More, our study suggests the involvement of WWOX in T2D-associated brain damage since Zfra1-31 treatment improved behavior and cognition, brain mitochondria function and oxidative stress.
The authors’ work is supported by ERD, through COMPETE 2020—Operational Programme for Competitiveness and Healthy Aging 2020 (CENTRO-01-0145-FEDER-000012); FCT under the projects PEst-C/SAU/LA0001/2013-
2014; EXPL/MED-FSL/0033/2021; UIDB/04539/2020; UIDP/04539/2020; CEECIND/02201/2017 and LA/P/0058/2020; ESCI exploratory research grant 2021.
AudienceTakeaway:
- High calorie diets increase the risk of T2D and, consequently, of dementia, particularly AD.
- WWOX is a new player in T2D-associated brain damage and represents a possible therapeutic target.
- Zfra1-31, a specific inhibitor of WWOX, has a therapeutic potential to fight T2D-associated brain damage.
