Transcript Lecture 12 Metals in brain

BIOMETALS IN
NEUROLOGICAL Function and
DISEASE
2+
Mn
2+
Fe
2+
Cu
2+
Zn
Our brains are full of
metals that are
absolutely vital, but
handled the wrong
way can be
devastating
Jonathan Knight
The brain is an organ
elaborated and functioning
from substances present in
the diet.
J.M Bourre
The brain concentrates
metals better than any other
tissue in the body.
Ashley Bush
Our brain does not work
properly without metals.
Why?
• Neurons release Zn at synapses to modulate
nerve impulses across synapses
Fe is required for myelin synthesis and
neurotransmitter release
• Cu, Zn, and Mn are cofactors for antioxidant
enzymes in the brain and other tissues
• Cu controls the activation and release of
neuropeptide hormones
Zn
(Zinc)
Atomic Wt. = 65.38
Atomic No. = 30
Valence
= Zn2+
1s22s22p63s23p64s23d10
1s22s22p63s23p63d10
Functions as a Modulator and Regulator
Zn is an essential neuromodulator
Zn
Zn is a potent neurotoxin
Zn is an “atypical” neurotransmitter
Free Zn2+ is found exclusively
in the presynaptic vesicles of
glutamatergic neurons in the
forebrain neurons of the
cerebral cortex
vesicular
zinc
Cerebellar cortex
It is not found in the cerebellar
cortex (Cer Cx)or thalamus
Control
ZnT-3 Knockout
Zn is concentrated in synaptic vesicles and
released in response to Ca2+
Zn2+
Zn
ZnT3
Zn in synaptic vesicles
is released into the
synaptic cleft, thereby
modulating the action
of glutamate
Ca2+
Zn
after Frederickson et al
Hilus of the Dentate Gyrus of
a Rabbit
Normal Hilus: Zn-neg or
healthy neurons (black) in
midst of Zn-pos axonal
plexus
CA/4 hilar region 24 hr after a
7 min ischemia. TSQ stain
(Zn-pos) are white
After Frederickson, 2004
What we should
know about Zinc
Most abundant “trace” mineral in brain
Zn
Background 3 nM, excitotory levels 10,000 times that
Contributes to excitotoxic brain injury after seizures,
stroke, and brain trauma
A deficiency enhances excitotoxicity of glutamate
An excess and deficiency induce apoptosis
Zn chelation is neuroprotective
Mn
(Manganese)
Atomic Wt. = 54.94
Atomic No. = 25
Valence
= Mn2+
What we should know about
Manganese
Mn
• Basically, a neurotoxin
• Neonatal exposure linked to attention
deficit syndrome in children
• Striatal dopamine depletion linked to
dietary and environmental Mn exposure
• Olfactory neuron entrance to brain
• Manganese superoxide dismutase, a
mitochondrial antioxidant enzyme
Fe
(Iron)
Atomic Wt. = 55.85
Atomic No. = 26
Valence
= Fe2+, Fe3+
What we should know
about Iron
Fe
• Myelin synthesis
• Thy1 synthesis (neurotransmitter release)
• Developmental processes in hippocampus
(apical dendritic morphology)
• Deposits in brain increase with age
• Synthesis of neuromelanin
Cu
(Copper)
Atomic Wt. = 63.54
Atomic No. = 29
Valence
= Cu+, Cu2+
What we should know
about Copper
•
•
•
•
•
•
Cu
Cu/Zn Superoxide dismutase
Neurotransmitter biosynthesis
Controls levels of dopamine
Controls norepinephrine biosynthesis
Controls the activity of PAM
Controls the biosynthesis and activity of at
least 18 neuropeptide hormones
• One of the most central metals in aging
Peptidylglycine-alpha
amidating monooxygenase (PAM)
O
Pep
C
H
N
C
H
Active
hormone
O
Cu
PAM
COOH
Pep
C
N
H
H
H
+
HOOC-CHO
glyoxylate
Galanin
Gastrin
(monoaminergic neurons)
(gastric acid)
Vasopressin
(water homeostasis)
Thyrotropin releasing
horomone
(thyroid hormone)
Pancreastatin
Neuropeptide Y
PAM
Cu
(Insulin control)
Gonadotropin releasing
hormone
(sex hormones)
(hunger, obesity)
Calcitonin
(osteoporosis)
Substance P
(emotions)
The Dark Side of Brain
Metals
Amyloid Diseases
“all neurodegenerative
diseases show amyloid
fibrils that have very similar
structures"
“fibrils are constituents of
plaques that are believed to be
linked to neurodegeneration”
Questions?
Are heavy metal ions responsible for the
formation of plaques? If so, how?
Are plaques toxic to neurons?
Are metals in plaques the toxic factor?
Parkinson’s Disease (one million)
James Parkinson (1817)
Lewy (1913) “Lewy bodies”
1996: Lewy bodies contained 3 proteins:
alpha-synuclein, parkin and ubiquitin
Tretiakoff (1919) “pigmented nerve cells in the
region called the substantia nigra” were lost in
Parkinson’s disease
Pigment due to neuromelanin: present in
substantia nigra and locus coeruleus
Fig. 1. Concentration of iron (ng/mg of wet tissue) in LC ({circ}) and in SN ()of human normal subjects
during aging
Fe
Substantia
nigra
Locus coeruleus
Zecca, Luigi et al. (2004) Proc. Natl. Acad. Sci. USA 101, 9843-9848
Copyright ©2004 by the National Academy of Sciences
Fig. 5. Concentration of copper (ng/mg of wet tissue) in LC of human normal subjects during aging
Cu
Locus coeruleus
Zecca, Luigi et al. (2004) Proc. Natl. Acad. Sci. USA 101, 9843-9848
Copyright ©2004 by the National Academy of Sciences
Alzheimer Disease
Amyloid precursor protein gives rise to plaques and
neurofibrullary tangles.
Fibrils composed of a protein called beta amyloid (A)
present in plaques
A has Cu binding sites; reduces Cu(II) to Cu(I)
Cu, Fe, Zn increase in neuropil and are highly
concentrated in plaques
In the presence of Zn and Cu, A aggregates into
amyloid which can be dissolved by metal chelators
Free radicals are believed responsible for neurotoxicity of A
Normal Staining of blood vessels
Zn Staining of blood vessels
In Alzheimer’s disease, synaptically released Zn
can interact with A protein causing it to
precipitate into plaques and around blood
vessels.
Plaques usually form in Zn-rich regions of the brain
and small amounts of Zn have been shown to
cause A to precipitate.
Ferrous Iron as a Pro-oxidant
OH- + HO .
H2O2 + Fe(II)
Hydrogen peroxide
.. ..
H : ..O : O
.. : H
Fe . (II)
Take home:
Free iron is dangerous
to biological systems
.. ..
H : O : .O : H
..
..
..
H : ..O :
Hydroxide ion
Ferrous iron
with unpaired
electron
. O.. : H
..
+ Fe(III)
Hydroxyl radical
Aging
Modified Protein
A possible
agenda for
Alzheimer’s
disease
Metal ions bind
Metal Chelators
Toxic Protein
Insoluble protein aggregates
Antibodies against
Neuron death
Conclusions
Divalent metal ions Zn, Mn, Fe, Cu are essential
for brain development, differentiation, function and
survival
Age-related disturbances in metal ion homeostasis
lead to dementias, impaired CNS functions
All metals are detrimental when elevated
Metals such as Fe and Cu can be pro-oxidants
Metals such as Cu, Fe may exert their neurotoxicity
through free radicals