Dolors Puigoriol Grup de Recerca en Neurofarmacologia
de l’envelliment – UB
Beneficial effects of 11β-HSD1 inhibition
on cognitive perfor-mancein a mouse
model of Alzheimer’s Disease
AgingAging is a multifactorial process characterized by a progressiveloss of physiological integrity leading to impaired functionaliy and increased vulnerability to death.
Ageing and Development. United Nations Development Programme. 2015 Nov Ageing and health. World Health Organization. 2015 Sept
Glucocorticoids and cognitionWhile aging, blood and cerebral glucocorticoid (GC) levels increase.
11β-HSD1 crystal structure (PDB ID 3LZ6).
RL-118
Alzheimer’s Disease Neurodegenerative disease
Progressive and irreversible
Cognitive decline accompained by emotional and behavioural disorders
Neuropathological alterations:
β-amyloid accumulation
Hyperphosphorylated Tau protein aggregates
Inflammation
Oxidative stress
Neuronal death
Aim
The objective of this project is to determine whetherthe inhibition of 11β-HSD1 enzyme ameliorates cog-nitive performance, even with a detrimental stimulussuch as metabolic stress through hypercaloric diet.
Experimental designRL-118 neuroprotective study in high-fat SAMP8mice model at 21mg/kg oral by gavage during 4weeks.
HFD consists on 60% of fatty-acids.
Beha
viour
alTe
stsCt
Ct+RL-118
HFDHFD+RL-118
WEAN High-Fat Diet
High-Fat Diet
RL-118 treatment
RL-118 treatment
1 month 2 months 3 months 4 months
Mole
cula
rAna
lysis
Behavioral tests
Novel Object Recognition Test
Morris Water Maze
3 chamber test
Molecular analysis
Western blot
qPCR
Novel Object Recognition Test
Habituation Familiarization
Memory test
ID=(TN-TO)/(TN+TO)
Behavioral resultsMorris Water Maze
submerged platform
Duration 6 days: Learning phase: submerged platform 5 days
Test: no platform
Different parameters related to time and distance in platform zone.
Three chamber test
Different parameters related to the timespent in each chamber.
Duration 20 minutes: Habituation: 10 min without
intruder mouse Sociability: 10 min with
intruder mouse
Tau pathology
Alzheimer’s News Today, 2014
Amyloid processing
Spies PE et al., 2012
Endoplasmic reticulum stress
Alasiri et al., 2018
p50
IkB
p65
Expression of inflammatorygenes (TNF-α , IL6)
Conclusions
SAMP8 mice treated with 11β-HSD1 inhibitor show changes in behavioural abilities, improving their cognitive performance, concretely the recognitionand spatial memory, and achieving better sociability behavior.
High-fat diet impairs recognition memory.
11β-HSD1 inhibitor treatment produce a reduction of neuropathological hallmarks of aging and AD, such as Tau pathology and amyloid processing.
Endoplasmic reticulum stress molecular pathway is activated after 11β- HSD1 inhibitor treatment to promote antioxidant defense and autophagy, as well as antiinflammatory activity.
THANK YOU!
Farmacologia
Dra Mercè PallàsDr Christian GriñánDra Anna M. CanudasFotini VasilopoulouVanessa IzquierdoJúlia CompanysTereza Cervinkova
Química Terapèutica
Dr Santiago VázquezDra Rosana Leiva