Beneficial effects of 11β-H SD1 inhibition on cognitive ... · Dolors Puigoriol . Grup de Recerca...
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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
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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
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Glucocorticoids and cognitionWhile aging, blood and cerebral glucocorticoid (GC) levels increase.
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11β-HSD1 crystal structure (PDB ID 3LZ6).
RL-118
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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
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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.
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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
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Novel Object Recognition Test
Habituation Familiarization
Memory test
ID=(TN-TO)/(TN+TO)
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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.
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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
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Tau pathology
Alzheimer’s News Today, 2014
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Amyloid processing
Spies PE et al., 2012
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Endoplasmic reticulum stress
Alasiri et al., 2018
p50
IkB
p65
Expression of inflammatorygenes (TNF-α , IL6)
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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.
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THANK YOU!
Farmacologia
Dra Mercè PallàsDr Christian GriñánDra Anna M. CanudasFotini VasilopoulouVanessa IzquierdoJúlia CompanysTereza Cervinkova
Química Terapèutica
Dr Santiago VázquezDra Rosana Leiva