Title : Autophagy changes in brain cells of 5-month-old db/db mice with diabetes type 2 and development of neurodegeneration
Abstract:
Dysregulation of autophagy have been shown in several diseases, like atherosclerosis (Yaribejgy et al., 2023), inborn lysosomal storage diseases (Francelle and Mazzulla, 2022) and diabetes Type 2 (Korolenko et al., 2021), concentrating attention at lysosomes as a potential target for therapy of several diseases (Rubinsztein et al., 2012; Wang et al., 2024). Simultaneously earlier it was shown, that autophagy in Type 2 diabetes was associated with the formation of features of Alzheimer disease (AD) (Korolenko et al., 2021). A common mechanism appears to be the impairment of autophagy, process which was not studied enough in brain cells - neurons and glial cells. A good opportunity to study the correction of diabetes and neurodegeneration is provided in db/db mice, genetic model of diabetes and obesity, developed sign of AD with ageing. In our previous work we have found that animals can be treated by some autophagy inducers, activating this process via mTOR -independent pathway (Pupyshev et al, 2022). In young (male 3-month-old db/db mice) autophagy inducer reduced obesity, attenuated hyperglycaemia, activated autophagy in the liver, heart and brain cells, weakened neuroinflammation and oxidative stress, restoring cognitive impairment (Korolenko et al., 2024). The aim of this work was to study in what extent the therapeutic effect of autophagy induction depends from the age of mice and autophagy gene transcription. Experiments were made in SPF vivarium of the Institute of Cytology and Genetics of RAS, Novosibirsk, Russia). The therapeutic effect of treatment by autophagy inductor (3% trehalose drinking, 30 days) was investigate in 5 months-old db/db mice. We studied Atg8 gene coding protein - marker of autophagy LC3-II, gene Becn 1 coding protein Becn 1, connected with autophagy and gene Insr. Trehalose drinking did not reduce the body weight or blood glucose and cholesterol level, but significantly decreased the expression of autophagy gene Atg8 and more significantly the insulin receptor gene Insr in brain cells. Thus, a different effect of autophagy induction was obtained for old 5-month-old db/db mice and young db/db mice, consisting in the absence of in the autophagy activation genes. It was concluded that autophagy activation in db/db mice was decreasing with age and became not effective in old 5-months old db/db mice.
