725 - Molecular neurobiology of disease
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Transcript of 725 - Molecular neurobiology of disease
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725 - Molecular neurobiology of disease
Parkinson’s disease Schizophrenia Alzheimer’s disease
Reference List
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Approaches epidemiology genetic
chromosome gene / protein
pharmacology anatomical
post-mortem MRI/PET
animal models
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Human Brain cut vertically down
midline
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Parkinson’s disease Loss of dopaminergic neurons
normal: 4% per decade Parkinson’s: 70-80% loss
normal Parkinson’s
substantia nigra
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Symptoms Hard to initiate
movement Interaction of
substantia nigra with cortex
see 746 lecture 6
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Therapy L-DOPA
cross blood-brain barrier dopamine agonists MAO-B inhibitors (selegiline = deprenyl) cell replacement
fetal midbrain transplants pigs carotid body stem cells
deep brain [=thalamus] stimulation
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Animal model Model with MPTP MPP+
Neuronal damage, activates microglia, which produce NO (iNOS), causes further neuronal damage
MPTP (1-methyl-4-phenyl -1,2,3,6-tetrahydropyridine)
MPP 1-Methyl-4-phenylpyridinium
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Causation Inherited disorder
-synuclein (folds SNAREs) Parkin (E3 ubiquitin ligase) DJ-1 (stress response chaperone) PINK-1 (mitochondrial protein kinase) *LRRK2 (another ?mitochondrial kinase) It is not clear why mutations in -
synuclein, or parkin or [] genes cause nigral dopaminergic cell death in familial PD [Le W & Appel SH (2004)]
*dominant – others are recessive
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Causation Environmental factors too
Rotenone fish poison blocks mitochondrial function upregulates -synuclein oxidises DJ-1
Paraquat
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One model
inhibitors of parkin
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Another model
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Summary Parkinson’s has
well-defined deficit – loss of dopaminergic cells
well-described pathology & behaviour variety of therapies no cure no known cause
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Schizophrenia Positive (hallucinations) & negative
symptoms (asociality) possibly several illnesses seasonal highly inherited
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Developmental disease genetic cause :
DISC1 or a chromosome translocation
caused by failure of neurons to migrate ?
red shows areas less in Sc
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Dopamine hypothesis positive symptoms respond to
treatment negative symptoms do not respond to
treatment DA antagonists
Chlorpromazine side effects, e.g. Parkinsonism,
constipation Haloperidol
D2 (+D3, D4 +5-HT2A) blocker
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Newer drugs e.g. clozapine dopamine D2 receptors and 5-HT action
D2 receptor block is key point e.g. mouse model
-ve symptoms from DA in prefrontal cortex
5-HT action helps -ve symptoms NMDA (glutamate) receptors blocked by
phencyclidine, relieves many symptoms
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Depression 5-HT (=serotonin)
main treatment is with uptake inhibitors
SSRI eg Prozac Noradrenaline
also selective re-uptake inhibitors
PFC: pre-frontal cortex
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Summary so far ethical issues “impede” research animal models hard to interpret key concept: neural diseases identified
with cellular / molecular deficit disease related to change in specific
neurotransmitter complexity of CNS leads to side effects
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Dementia Reduction of brain volume and cells
with age Dementia increases with age
at 65, 11% of USA had dementia 70% of dementia is Alzheimer’s 15% from strokes
at 85, 47% affected Early onset Alzheimer’s inherited
<1% of cases
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Alois Alzheimer On November 3, 1906, Alois Alzheimer
gave a lecture to the Meeting of the Psychiatrists of South West Germany, presenting the neuropathological and clinical description of the features of one of his cases, Auguste D., who had died of a dementing illness at the age of 55,
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Alzheimer’s Symptoms Forgetfulness untidiness confusion less movement storage of new memory reduced finally loss of bodily function
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Neuroanatomy cortex very reduced
normal Alzheimer
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Neuroanatomy cortex reduced - note gaps between
folds
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Neurodegeneration brains feature
plaques(A =-amyloid)
tangles(tau)
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Neurofibrillary tangles micrograph drawing by Alois
Alzheimer
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Development of tau
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Amyloid hypothesis Down’s syndrome leads to AD by 40
linked to chromosome 21 Positional cloning identified: amyloid- (A) peptide 40-42 amino
acids families with mutations in APP
670 / 692 / 716 & 717 amyloid toxic to cultures
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Presenilins Familial early onset dominant AD
linked to mutations on chromosomes 14 & 1 presenilin I : mutations lead to onset at
age 28 presenilin II : second homologous gene
mutations are in regions conserved between PSI
and PSII associated with AD lead to increased A production
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Presenilins code for two secretases and involved in processing APP
secretase now called ADAM secretase called BACE
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Proteolysis of APPNormal
amyloidogenic
APP
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Proteolysis of A In non-familial AD, plaques caused not
by production of A but by failure to degrade it
Little evidence for increased production of A peptide
maybe normally degraded quickly half life 1-2 hr
tangles resistant to degradation enzymes:
neprilysin & insulin-degrading-enzyme
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Neprilysin
Neprilysin knockout mice have more A
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how does faulty -amyloid lead to tangles of tau?
tau is hyperphosphorylated
GSK-3 glycogen synthase kinase
Major problem
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More direct interaction? tau and A form complexes GSK-3 phosphorylates tau in complex
tau A Ais extracellular
in neurons
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tau v A AD has both tau and A other diseases have just tangles of tau
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Apolipoprotein E Another family gene for late onset of
AD produces Apolipoprotein E
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Apolipoprotein E - cont receptor (LRP) expressed in astrocytes normal role is in cholesterol transport may aid in clearance of -amyloid from
brain to blood mutations disrupt clearance
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Oxidative stress main function of -amyloid may be to
protect cells from reactive Oxygen radicals
damage to mitochondria leads to *OH shortage of energy (or oxygen)
increases likelihood of AD through high [Ca]
metal ions might affect build up of -amyloid
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Therapy ?? cholinergic therapy secretase blockers relief of oxidative stress Apolipoprotein therapy stem cells for replacement vaccination ginko biloba
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Cholinergic hypothesis cholinergic neurones in basal forebrain
project to cortex and hippocampus muscarinic antagonist, (M1),
pirenzipine, causes memory loss in hippocampus
agonists, e.g. physostigmine, improve memory
But other systems interact
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Cholinergic therapy Cholinesterase inhibitors – delay
symptoms Tacrine: allosteric – 1993 (toxic in liver) Donepezil; mixed binding
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Try Cholinergic agonist M2 on basal ganglia and intestine
Depletion of M1 receptors? M1 and M3 receptors in hippocampus
Drug trials discontinued
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Summary of AD Full mechanism not known
amyloid hypothesis well – established role of tau also established role for glia and neurons
No one effective treatment cholinotherapy promising ?
Happy Christmas & New Year!