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