ALTERATO METABOLISMO DEL COLESTEROLO NELLA … · COLESTEROLO NELLA MALATTIA DI ALZHEIMER Dott.ssa...
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A LT E R ATO M E TA B O L I S M O D E L COLESTEROLO NELLA MALATTIA DI ALZHEIMER
Dott.ssa Paola Gamba Dipartimento di Scienze Cliniche e Biologiche, AOU San Luigi Gonzaga, Orbassano (TO) Università degli Studi di Torino
A vicious circle in Alzheimer’s disease
NFT: neurofibrillary tangles
Oxidized cholesterol as the driving force behind t h e d e v e l o p m e n t o f Alzheimer's disease. Gamba P et al., 2015 Front Aging Neurosci. 2015 7:119
Ø Hypercholesterolemia is unanimously recognized to be a risk factor for sporadic AD (Strand et al., 2013).
Ø The high fat diet (HFD) induces cognitive decline in animal models for AD (Knight et al., 2014).
Ø Altered cholesterol metabolism plays a role in the development and in the progression of AD (Gamba et al., 2015). Ø Cholesterol-lowering agents belonging to the family of statins reduce the prevalence of AD (McGuinness et al., 2014).
NEURON
LXR
24-OHApoE
HMG-CoA
BloodorCSF
24-OH24-OH
ApoEChol
Chol
Chol
ASTROCYTE
LRP1
Cholesterol homeostasis in the brain
T h e l i n k b e t w e e n a l t e re d cholesterol metabolism and Alzheimer's disease. Gamba P et al., 2012 Ann N Y Acad Sci. 1259:54-64.
Fluxes of oxysterols across the blood brain barrier
Oxidized cholesterol as the driving force behind the development of Alzheimer's disease. Gamba P et al., 2015 Front Aging Neurosci. 2015 7:119
The role of oxysterols in vascular ageing. Gargiulo S et al., 2016 J Physiol. 594(8):2095-113
Oxysterol levels during AD progression
b c
a
Stage II Stage IV Stage VI
Early AD (stages I-II)
Late AD (stages IV-VI)
Oxysterol levels during AD progression
Control Oxysterol Mix 10µM 24h
3h 12h 24h
42 kDa -
50 kDa -
25 kDa -
Oxysterol Mix 10µM
Serpin A3N
Lcn2
β-actin 0
100
200
300
400
500
Control 3h 12h 24h
Lcn2
/β-a
ctin
**** ****
0
100
200
300
Control 3h 12h 24h
Serp
inA
3N/β
-act
in
*** ****
GFAP/DAPIOxysterol-induced astrocyte reactivity
24-OH
0
1
2
3
4
Fold
indu
ctio
n
*** ** *** *** ***
Con
trol
CD
36
β1-in
tegr
in
IL-8
MC
P-1
MM
P-9
27-OH
Fold
indu
ctio
n
0
1
2
3
4
***
*** ***
***
***
Con
trol
CD
36
β1-in
tegr
in
IL-8
MC
P-1
MM
P-9
Oxysterol-induced neuroinflammation
SH-SY-5Y cells
**(p<0,01), ***(p<0,001) vs control
Effect of 24-OH in potentiating Aβ neurotoxicity
CD36 CD47β1
Neuron
control 27-OH (1 µM) + Aβ1-42 (1 µM)
24-OH (1 µM) + Aβ1-42 (1 µM)
Congo red staining of Aβ binding
Oxysterols: 48 hs Aβ1-42: 8 hs
SK-N-BE cells
Aβ
0
1
2
3
4
Control 24-OH 1 µM
27-OH 1 µM
pg Aβ/
mg
prot
eins
*** *** SK-N-BE cells
Effect of 24-OH and 27-OH on Aβ1-42 production
*** significantly different vs. control (p<0.001)
↑ APP ↑ BACE1 ↑ CTF-PS1
Neuroprotective effect of 24-OH
Effect of 24-OH on phospho-tau accumulation
SK-N-BE cells
24-OH ↑ SIRT1 ↓ acetyl-tau
↓ phospho-tau
↓ tau
↑ ROS
Control 24-OH 1 µM
SIRT1 (3 hours)
α-tubulin
24-OH 1 µM
6h 15h 24h
phospho-tau
phos
pho-
tau
(%)
0
50
100
150
*** ***
24-OH 1 µM
6h 15h 24h
Beneficial effect of 24-OH in vivo
Amyloid β1-42
tau-pathology
24-OH + Amyloid β1-42
NEUROPROTECTION
phospho-tau
β-actin
ALTEREDCHOLESTEROLMETABOLISM
Senileplaques
Neurofibrillarytangles
NeuroinflammationOxidativestress
Neuroprotection
Astrocytereactivity
Braininsulinresistance
Prof. Gabriella Leonarduzzi
Prof. Giuseppe Poli
Prof. Fiorella Biasi
Dr. Gabriella Testa
Dr. Erica Staurenghi
Dr. Barbara Sottero
Dr Serena Giannelli
Dr. Simona Gargiulo
Dr. Daniela Rossin
Dr. Noemi Iaia
Prof. Luigi Iuliano Department of Medico-Surgical Sciences and Biotechnology
Sapienza University of Rome
Dott. Giorgio Giaccone Foundation IRCCS Institute of Neurology
Carlo Besta, Milan
Prof. Elena Tamagno Department of Neuroscience Rita Levi Montalcini
University of Turin