Enfermedades neurodegenerativas
y acumulación de hierro.
Dr. Miguel Arredondo Olguín
INTA, Universidad de Chile
II JORNADAS INTERNACIONALES PROGRAMA DE INVESTIGACIÓN DE
EXCELENCIA INTERDISCIPLINARIA EN ENVEJECIMIENTO SALUDABLE
(PIEI-ES)
Talca, Noviembre, 2014
IMPORTANCIA DEL HIERRO
TRANSPORTE
De OXIGENO
Hb, Mb
TRANSFERENCIA
De e*
Citocromos
ALTA TOXICIDAD
+ H2O2  Fe3+ + OH° + OHFe3+ + NADH  Fe2+ + [NADH°+]
Fe2+
PROTEINA
ENZIMAS. Fe-S
Catalasa Peroxidasa
Hidrolasa
ALTA REACTIVIDAD
CAPACIDAD PARA CAPTAR e*
-OH-, -COOH, NH2, -SH
Esencialidad vs Toxicidad
Esencialidad: Anemia por deficiencia de hierro
Poblaciones susceptibles
HIERRO, VIDA Y EVOLUCIÓN
Primera paradoja:
“ESCASEZ EN PLENA ABUNDANCIA”
 Los seres vivos necesitan poco hierro
 El hierro abunda en la biosfera
 El hierro en atmósfera oxidante es poco soluble
 A pesar de la abundancia de hierro en la biosfera
su bio-disponibilidad es muy baja.
 Los seres vivos han de ser capaces de “disolver” el
hierro para poder asimilarlo.
Segunda Paradoja:
“El nutriente más tóxico”:
“El estrés oxidativo”
 El Hierro es potencialmente tóxico en ambientes donde abunda el O2.
 La concentración de hierro intracelular ha de estar controlada.
 Origen de la toxicidad del Fe: la reacción de Fenton:
Fe (II) + H2O2 ----> Fe (III) + OH - + .OH
¡Dos veces más potente
que la lejía !
 El hierro “libre” intracelular se relaciona directamente con el estrés
oxidativo y sus consecuencias patológicas.
 La toxicidad del hierro en ambientes aerobios se manifiesta en todos los
seres vivos .
 Los seres de vida aerobia disponen de mecanismos que atenúan efectos
del estrés oxidativo.
IMPORTANCIA DEL HIERRO
TRANSPORTE
DE OXIGENO
Hb, Mb
PROTEINA
ENZIMAS. Fe-S
TRANSFERENCIA
DE e*
Citocromos
ALTA TOXICIDAD
Fe2+ + H2O2  Fe3+ + OH° + OHFe3+ + NADH  Fe2+ + [NADH°+]
Catalasa Peroxidasa
Hidrolasa
ALTA REACTIVIDAD
CAPACIDAD PARA CAPTAR e*
-OH-, -COOH, NH2, -SH
[Fe]
[Fe]
Esencialidad vs Toxicidad
HOMEOSTASIA DEL HIERRO
Balance coordinado entre captación, utilización y almacenamiento intracelular
Metabolismo del Hierro
 Increased iron stores and inflammation induce hepcidin synthesis
 Suppression: hypoxia, anemia, increased and/or ineffective erythropoiesis in bone marrow.
 Hepcidin is induced under infection, decreasing the available host iron pool that is essential for
survival of invading pathogens.
MECANISMOS DE REGULACIÓN
Hepcidin
Iron and hepcidin: a story of recycling and balance
Clara Camaschella. Hematology 2013
Lum en
Hem
HCP1
A pical
Absorción
de
Fe hem
Hem
H O -1
F e(II)
LIP
FLVC R
Basolateral
Hem
Hpx
C irculación
Figure 2. Effect of age on body iron.
All values for body iron are positive and indicate the
amount of storage iron. Data are based on a convenience
sample of 2057 specimens collected in NHANES III. Shaded
areas represent the mean 1 SEM for each 5-year interval.
Figure 3. Cumulative frequency distributions of body iron
calculated from the ratio of the serum transferrin receptor
to serum ferritin.
The clear area and positive values indicate storage iron, and
the shaded area and negative values indicate tissue iron
deficiency. Data are shown for pregnant Jamaican women
aged 16-35 years, US women aged 20-45 years, and US men
aged 20-65 years.
¿Cuál es la relación entre metabolismo de Fe
y Sindróme Metabólico y diabetes?
RNAm Ferritina
Intracelular
Internalización
de Insulina
y Acciones
Biológicas
Insulina
+
Ferritina
+
Fe+2
+
Fe+2
Transferrina
+
-
Transferrina
Fe libre
Glicaciónde
proteínas
Estrés
oxidativo
Extracelular
RTf
Hiperinsulinemia
Insulino resistencia
Reactividad Vascular anormal
Daño celular y tisular
 Hiperglicemia
GLICOLISIS
Glucosa
Fructosa-6P
Gliceraldehido 3-P
1,3 Difodfoglicerato
Piruvato
Glicación
de SOD y Catalasa
(↑ H2O2)
Formación
de AGEs
Glicación de Transferrina
Glicación de
Proteínas
 Activación de NADPH
oxidasa (↑ O2.- )
 Activación de Nf-κB
 (↑ NOS, NO, ONOO - )
AGEs
RAGE
 Cadena Transportadora de electrones en
la Mitocondria.
Fe y Diabetes
No solo altos niveles de Fe se han asociado a DM2
(Arredondo et al., AJCN, 2007)
HEM
HO-1
Fe + CO2 + Biliverdina
Polimorfismo en el promotor de la
HO-1 de repeticiones (GT) n
Pacientes DM2 portadores
de repeticiones cortas
> niveles de Ferritina
> actividad de HO-1
 complicaciones por estrés oxidativo
Parámetros hematológicos: niveles de Fe
DM2
SM
C
Hb (g/dL)
Fe (mg/dL)
FS (µg/L)&
RTf (mg/L)&
HO&
14,0 ± 1,4
14,2 ± 1,4
13,8 ± 1,5
NS
128,3 ± 52,8
126,5 ± 44,5
108,2 ± 37,5
< 0,002
61 (35-107)#
52 (27-100)#
34 (15-76)#
< 0,001
5,5 ± 2,0
6,3 ± 1,7
6,8 ± 2,7
< 0,001A
0,7 (0,3-2,0)#
0,6 (0,2-1,7)#
0,3 (0,1-0,7)# < 0,001
(nmoles bilirrubina/mg proteína/hr)
# : Diferencia estadística entre Mujeres/grupos
&: Promedio geométrico + rango
A: Diferencia estadística entre DM2 y C
Iron Nutrition and oxidative stress parameters in studied subjects
Control
n=146
15.7±1.3
OB
n=132
16.2±1.2a
T2D
n=60
14.7±1.8c
T2DOB
n=106
15.3±1.6
Serum Ferritin (µg/L)1
56.5
(33.7-90.9)
75.5c
(50.0-111.0)
70.3b
(42.2-118.1)
82.3c
(53.9-125.7)
Serum Fe (µg/dl)
107.5±37.4
100.2±35.1
124.2±88.2
107.9±50.7
Transferrin Saturation (%)
32.7±12.0
30.5±9.0
35.6±15.9
27.9±9.7a
Transferrin Receptor (µg/mL)1
TBI (mg/kg)
2.8
(1.2-6.4)
8.5±3.2
3.9
(1.3-6.6)
9.7±3.3a
3.6
(1.8-7.4)
9.1±3.7
3.6
(1.9-6.5)
9.6±2.7a
Hepcidin (ng/mL)
19.0±8.7
25.0±11.5a
23.4±10.6a
25.2±10.8b
RBP4 (µg/mL)
hsCRP (µg/dl)1
26.1±8.4
0.8
(0.2-4.4)
2.6
(0.9-7.1)
0.99
(0.4-2.4)
33.6±7.3a
1.8
(0.5-6.8)
4.2a
(1.7-10.1)
1.4a
(0.7-2.7)
31.7±9.6a
1.9b
(0.4-7.8)
4.6c
(1.7-12.4)
1.7b
(1.0-3.1)
32.7±9.3a
2.0b
(0.4-9.0)
3.4
(0.4-9.0)
2.1c
(1.2-3.5)
Hemoglobin (g/dl)
HO-1 (nmole bilirubin/mg protein/h)1
TBARS (nmoles/mL)1
TBI: Total body iron; RBP4: Retinol Binding protein 4; hsCRP: high-sensitivity C reactive protein; HO-1: heme oxygenase-1; TBARS: Thiobarbituric Acid Reactive Species.
Values are mean ± SD; 1Values are geometric mean±(Range)
One way ANOVA, post hoc Dunnett`s ap<0.05; bp<0.01; cp<0.001
Table 3
Risk of developing type 2 diabetes (OR) according to
ferritin quartiles and TBARS concentration.
OR without
to adjust
CI
p
OR
adjusted*
CI
P
Ferritin Q1: <50 μg/L
1.000
Ferritin Q2: 50-100 μg/L
1.021
0.42-1.71
0.12
1.101
0.87-1.57
0.66
Ferritin Q3: 100-150 μg/L
1.302
0.45-1.91
0.09
1.133
0.66-1.83
0.08
Ferritin Q4: 150-200 μg/L
1.377
0.97-2.19
0.07
1.782
1.61-1.92
<0.01
TBARS
1.980
1.91-2.28
<0.05
2.250
1.89-3.25
<0.05
* Adjusted to age, BMI and hsCRP
OR were estimated through logistic regression
1.000
Table 4:
Risk of developing type 2 diabetes (OR) according to
hepcidin expression quartiles
OR
CI
p
OR
CI
p
Adjusted*
Hepcidin Q1
1.000
1.000
Hepcidin Q2
1.483
1.11-1.98
0.007
1.300
0.95-1.11
0.470
Hepcidin Q3
1.980
0.89-4.37
0.091
2.120
0.89-5.03
0.087
Hepcidin Q4
3.291
1.39-7.75
0.006
4.370
1.67-11.42
0.003
* Adjusted to age, BMI and hsCRP
OR were estimated through logistic regression.
3`
5`
120
GTn
C
MS
OB
DM
DMOB
175
210
189
172
109
Total
855
Micro-polimorfismo
S = < 27 (GT)n
M = 27-32 (GT)n
L = >32 (GT)n
Nº Individuals
HO
100
80
60
40
20
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
GT Repetitions
GENOTIPO (%)
Frecuencia alélica(%)
S
6.2
8.0
7.9
7.6
8.3
M
9.6
10.9
8.9
8.7
8.0
L
4.2
1.1
3.1
3.7
3.7
C
MS
OB
DM
DMO
B
Hardy-Weinberg Equilibrium
C
MS
OB
DM
DMOB
SM
7.8
13.7
12.3
10.8
7.5
SL
2.3
0.4
1.1
2.1
1.8
ML
0.8
1.2
1.9
1.6
1.3
MM
5.5
6.0
2.8
2.6
0.7
SS
1.3
2.8
2.1
1.2
0.7
LL
2.7
0.6
2.0
1.9
0.8
***
***
10
C
OB
C
T2D
***
50
20
***
C
250
***
30
10
**
5
OB
D
T2D
***
200
T2DOB
***
150
100
50
0
0
C
TLR-4 mRNA
***
30
0
T2DOB
40
30
B
10
5
60
Values are mean ± SEM.
Data were analyzed using the
Kruskal-Wallis test.
*p<0.05; **p<0.01; ***p<0.001.
IL-6 mRNA
15
TLR-2 mRNA
Hepcidin;
IL6;
NF-B;
TLR-2;
TLR-4;
TNF-.
40
*
OB
T2D
C
T2DOB
20
E
**
***
***
TNF-α mRNA
A)
B)
C)
D)
E)
F)
A
0
NF-kB mRNA
Figure 1: Relative
abundance of genes
related to inflammation in
OB, T2DOB, T2D and Cn
subjects.
Hepcidin mRNA
20
20
10
0
F
OB
***
T2D
***
15
T2DOB
***
10
5
0
C
OB
T2D
T2DOB
C
OB
T2D
T2DOB
Hierro y cerebro.
 Es importante para la función neuronal.
 Funciones:
 Es un componente esencial del citocromo a, b y c
oxidasa.
 Componente del complejo hierro – sulfuro de la
cadena oxidativa.
 Es un cofactor para la tirosina, triptófano
hidroxilasa, ribonucleótido reductasa, succinato
deshidrogenasa y aconitasa.
 Es esencial para síntesis de lípidos, colesterol
y un rol en el sistema GABA.
 Existen altas concentraciones en globo pálido,
sustancia nigra, núcleo dentado y corteza
motora.
 Las neuronas lo almacenan como Ferritina de
cadena liviana o pesadas.
 La alteración de Ferritina (por inserción de
adenosina) produce la “neuroferritinopatía”.
 Existen múltiples vías de regulación para el
metabolismo del hierro
Lista de enfermedades neurodegenerativas
 Enfermedad de Alzheimer
 Demencia con cuerpos de Lewy
 Demencia frontotemporal
 Demencia mixta (multi-infarto y E. de Alzheimer)
 Enfermedad de Parkinson
 Atrofia Multisistémica
 Parálisis supranuclear progresiva
 Degeneración córticobasal
 Esclerosis lateral amiotrófica.
 Enfermedad de Creutzfeldt-Jacob.
Desordenes asociados con neurodegeneración y
anormalidades en la regulación del hierro que
resultan depósitos de hierro en el cerebro.
Desordenes asociados a depósitos de hierro primarios con
anormalidades genéticas en las vías metabólicas del hierro.
 Neuro-degeneración asociada a la pantotenato kinasa (PKAN)
 Hipo-prebetalipoproteinemia, acantosis y retinitis pigmentosa con
degeneración del pallidal (HARP)
 Neuro-degeneración con acumulación de hierro en cerebro (NBIA)
 Neuro-ferritinopatía
 Aceruloplasminemia
 Hemocromatosis
Desordenes con cambios secundarios en las vias regulatorias
del metabolismo de hierro
 Enfermedad de Huntington
 Enfermedad de Parkinson
 Friedreich´s ataxia.
Inflammation
NFB activation
Infl cytokines
FIGURE 1 | Inflammation causes ROS/RNS production, mitochondrial dysfunction, and iron accumulation. Inflammation,
oxidative damage, and mitochondrial dysfunction are common features of neurodegenerative diseases. A complex net of
relationships connect these features, which through feedback mechanisms contribute to the evolvement of neuronal death.
Dementia with Lewy bodies (DLB)
Fig. 1. Expression levels of
several iron metabolism
genes in patients with AD
compared with controls.
The distribution of the expression
levels of (A) TFRC (B) TFR2 (C)
SLC40A1 (D) HAMP and (E)
SLC11A2 of patients with AD and
control subjects are represented by
the box-plots.
The quantification was performed
by normalizing the sample to a pool
of individuals and using HPRT1 as a
housekeeping gene. Dots represent
the mild outliers. The number of
individuals analyzed is indicated in
brackets. p-values were obtained by
covariance analysis.
Fig. 2 Macrophages migrating into the brain release nitric oxide radicals (NO•), a process that
involves the catalytic oxidation of ferrous iron. NO• is capable of diffusing pass the cellular
membranes and into neurons where it can react with superoxide (O2•−) and promote formation of
the highly reactive and toxic peroxynitrite (ONOO−)
Fig. 4 Extravasated macrophages phagocytose and degrade damaged neurons
and subsequently die to terminate their function, which leads to the release
of iron into the extracellular space of the CNS on a low molecular weight form
Fig. 5 The macrophages, like monocytes and microglia, are capable of secreting hepcidin into the brain
extracellular space. Hepatic hepcidin is synthesized in response to inflammatory signals and secreted into
blood plasma from where it can diffuse into the brain in areas with a compromised blood–brain barrier. The
hepcidin is capable of binding and inhibiting ferroportin needed for export of iron from neurons, which may
result in neuronal iron accumulation and increased the likelihood of neuronal damage via Fenton chemistry
Fig. 6 Potential pharmacological intervention points to inhibit the impact of
migrating macrophages on their deposition of iron in the brain.
a) Inhibition of monocytes migration into the brain via transfer through the brain
capillaries.
b) Inhibition of the functioning of the brain macrophages for phagocytosis and nitric oxide
(NO•) release.
c) Extracellular chelation of low molecular weight iron released from dying macrophages.
d) Intracellular chelation of iron in neurons subsequent to their uptake of low molecular
weight iron from the extracellular space
REDUCING IRON IN THE BRAIN: A NOVEL PHARMACOLOGIC MECHANISM OF HUPERZINE A IN
THE TREATMENT OF ALZHEIMER’S DISEASE. Xiao-Tian Huang. Neurobiology of Aging 35 (2014) 1045
Fig. 6. A hypothetical scheme for the pharmacologic mechanisms of Huperzine A (HupA) in the treatment of Alzheimer’s disease. In addition to
acting as an acetylcholinesterase inhibitor, Huperzine A (HupA) has the ability to inhibit transferring receptor 1 (TfR1) expression and then
reduce transferrin-bound iron (TBI) uptake by the neurons or other brain cells which has TfR1 expression on the membrane. This will lead to
progressive reduction in iron contents in the brain and thus protecting neurons and other brain cells from damage and apoptosis probably by
inhibiting the iron-associated oxidative stress. “Reducing iron in the brain” is a novel pharmacologic mechanism of HupA in the treatment of
Alzheimer’s disease. Abbreviations: HupA, Huperzine A; TBI, transferrin-bound iron; TfR1, transferring receptor 1.
Low-copper diet as a
preventive strategy for
Alzheimer’s disease
Rosanna Squitti , Mariacristina
Siotto , Renato Polimanti
Neurobiology of Aging
DOI: 10.1016/j.neurobiolaging.2014.02.031
Low-copper diet as a
preventive strategy for
Alzheimer’s disease
Rosanna Squitti , Mariacristina
Siotto , Renato Polimanti
Neurobiology of Aging
DOI: 10.1016/j.neurobiolaging.2014.02.031
Fig. 1. Biochemical basis of the theoretical
model of copper toxicity in AD.
b-APP binds and reduces copper from Cu(II) to
Cu(I),
which
modulatescopper-induced
toxicity based on redox reactions through the
production of H2O2,triggering chain reactions
of oxidative stress and lipid peroxidation.
A and metalsare packed together in plaques,
and it has been postulated that A plaques
disturbneuronal physiology, entrapping metals
within the plaques, while cell-associatedcopper
could be decreased.
On this basis it could be assumed that
decopper-ing agents, as for example zinc
therapy, can reduce systemic Non-Cp copper
andstop the feeding of noxious copper entering
redox cycles with A,
thus halting
theprogression of A plaques and promoting
their solubilization.
Additionally, metalionophores can improve
neuroregenerative processes, restoring the
physiologicaluptake of metals in neurons,
which would suffer because of the copper
entrappedwithin the extracellular A plaques.
Copper subtype of Alzheimer’s disease (AD): Meta-analyses, geneticstudies and predictive
value of non-ceruloplasmim copper in mildcognitive impairment conversion to full AD
Rosanna Squitti, JTEMB, 2014
En resumen…….
1) Existe asociación entre el metabolismo del
hierro y Enfermedades neurodegenerativas
2) Elemento común desencadenador:
Eje Inflamación – Hepcidina
3) Elemento mediador: Estrés Oxidativo
4) Consecuencia final: Muerte Celular
“Muchas gracias
por su atención”
Mónica Andrews, PhD (INTA)
Valeria Candia, MSc (INTA)
Dr. Manuel Olivares (INTA)
Dr. Néstor Soto (Hospital Arriarán)
Solange Le Blanc , PhDc (Suiza)
Alejandra Espinoza, PhDc
Marcela Fuentes, PhD (PUC)
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Enfermedades neurodegenerativas y acumulación de hierro. Dr