Frailty in 6XFAD mouse model of Alzheimer’s disease: The influence of age and proteasome activation
The increase in frailty is associated with the progression of Alzheimer’s disease (AD), one of the most common age-related neurodegenerative disorders worldwide. AD is characterized by the accumulation of amyloid plaques composed of aggregated amyloid-beta (Abeta) peptides, mainly Abeta 42. In the same time, dysfunction of the ubiquitin-proteasome system responsible for the removal of proteins has
been observed during aging and in age-related disorders like AD. A proteasome activator, 18 alpha- glycyrrhetinic acid (18-alpha GA), has been shown to enhance levels of proteasome activities and to decrease Abeta deposits in model organisms. We examined the effect of 18-alpha GA supplementation on APP processing and generation of Abeta 42 in the 5xFAD transgenic AD mouse model. This is an early-onset AD mouse model characterized by the deposition of plaques in the cortex and hippocampus as early as at 2 months of age. We exposed both female and male mice to the proteasome activator 18-alpha GA treatment for one month, starting from 2-months of age, when animals already have developed plaques. This is considered an early phase of AD pathology, known to be suitable for therapeutics application. We determined frailty in young (2 months of age) and old (12-13 months of age) 5xFAD mouse, as well in those treated with 18-alpha-GA. Both female and male mice were tested in the open field test, rope test and grip strength test. Body weight was also measured and clinical signs of deterioration in aging were scored. All together these parameters were used to determine frailty in 5xFAD. Obtained results showed a significant increase in frailty in the aged 5xFAD mice. Significant differences were observed between males and females. 18-alpha-GA treatment increased activity of the proteasome in the cortex and hippocampus of 5xFADmice and decreased the number of Abeta plaques.
Results indicated potential therapeutic use of 18-alpha-GA.
been observed during aging and in age-related disorders like AD. A proteasome activator, 18 alpha- glycyrrhetinic acid (18-alpha GA), has been shown to enhance levels of proteasome activities and to decrease Abeta deposits in model organisms. We examined the effect of 18-alpha GA supplementation on APP processing and generation of Abeta 42 in the 5xFAD transgenic AD mouse model. This is an early-onset AD mouse model characterized by the deposition of plaques in the cortex and hippocampus as early as at 2 months of age. We exposed both female and male mice to the proteasome activator 18-alpha GA treatment for one month, starting from 2-months of age, when animals already have developed plaques. This is considered an early phase of AD pathology, known to be suitable for therapeutics application. We determined frailty in young (2 months of age) and old (12-13 months of age) 5xFAD mouse, as well in those treated with 18-alpha-GA. Both female and male mice were tested in the open field test, rope test and grip strength test. Body weight was also measured and clinical signs of deterioration in aging were scored. All together these parameters were used to determine frailty in 5xFAD. Obtained results showed a significant increase in frailty in the aged 5xFAD mice. Significant differences were observed between males and females. 18-alpha-GA treatment increased activity of the proteasome in the cortex and hippocampus of 5xFADmice and decreased the number of Abeta plaques.
Results indicated potential therapeutic use of 18-alpha-GA.
