725 - Molecular
neurobiology of disease
 Parkinson’s disease
 Schizophrenia
 Alzheimer’s disease
 Reference List
Approaches
 epidemiology
 genetic
 chromosome
 gene
/ protein
 pharmacology
 anatomical
 post-mortem
 MRI/PET
 animal models
Human Brain
 cut vertically down
midline
Parkinson’s disease
 Loss of dopaminergic neurons
 normal:
4% per decade
 Parkinson’s: 70-80% loss
normal
substantia nigra
Parkinson’s
Symptoms
 Hard to initiate
movement
 Interaction
of
substantia nigra
with cortex
see 746 lecture 6
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
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-4phenylpyridinium
Causation
 Inherited disorder
 *a-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 a-synuclein, or
parkin or [] genes cause nigral dopaminergic cell
death in familial PD [Le W & Appel SH (2004)]
*dominant – others are recessive
Causation
 Environmental factors too
 Rotenone
 fish
poison
 blocks mitochondrial function
 upregulates a-synuclein
 oxidises DJ-1
 Paraquat
One model
inhibitors
of parkin
Another model
Summary
 Parkinson’s has
 well-defined
deficit – loss of dopaminergic
cells
 well-described pathology & behaviour
 variety of therapies
 no cure
 no known cause
Schizophrenia
 Positive (hallucinations) & negative
symptoms (asociality)
 possibly several illnesses
 seasonal
 highly inherited
Developmental disease
 genetic cause :
 DISC1
or a chromosome translocation
 caused by failure of neurons to migrate ?
 red
shows
areas less
in Sc
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
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
Depression
 5-HT (=serotonin)
 main
treatment is
with uptake
inhibitors
 SSRI eg Prozac
 Noradrenaline
 also
selective reuptake inhibitors
PFC: pre-frontal cortex
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
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
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,
Alzheimer’s Symptoms
 Forgetfulness
 untidiness
 confusion
 less movement
 storage of new memory reduced
 finally loss of bodily function
Neuroanatomy
 cortex very reduced
normal
Alzheimer
Neuroanatomy
 cortex reduced - note gaps between folds
Neurodegeneration
 brains feature
 plaques
(Ab =
b-amyloid)
 tangles
(tau)
Neurofibrillary tangles
 micrograph
drawing by Alois Alzheimer
Development of tau
Amyloid hypothesis
 Down’s syndrome leads to AD by 40
 linked
to chromosome 21
 Positional cloning identified:
 amyloid-b (Ab) peptide 40-42 amino acids
 families
 670
with mutations in bAPP
/ 692 / 716 & 717
 amyloid
b toxic to cultures
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 Ab production
Presenilins
 code for two secretases b and g
 involved in processing bAPP
b
a
g
a secretase now called ADAM
b secretase called BACE
Proteolysis of APP
Normal
amyloidogenic
APP
Proteolysis of Ab
 In non-familial AD, plaques caused not by
production of Ab but by failure to degrade it
 Little evidence for increased production of
Ab peptide
 maybe normally degraded quickly
 half
life 1-2 hr
 tangles resistant to degradation
 enzymes:
 neprilysin
& insulin-degrading-enzyme
Neprilysin
 Neprilysin knockout
mice have more Ab42
Major problem
 how does faulty b-amyloid lead to tangles of
tau?
 tau is
hyperphosphorylated
 GSK-3 glycogen
synthase kinase
More direct interaction?
 tau and Ab form complexes
 GSK-3 phosphorylates tau in complex
tau
Ab
in neurons
Ab is
extracellular
tau v Ab
 AD has both tau and Ab
 other diseases have just tangles of tau
Apolipoprotein E
 Another family gene for late onset of AD
produces Apolipoprotein E
Apolipoprotein E - cont
 receptor (LRP) expressed in astrocytes
 normal role is in cholesterol transport
 may aid in clearance of b-amyloid from
brain to blood
 mutations disrupt clearance
Oxidative stress
 main function of b-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 b-amyloid
Therapy ??
 cholinergic therapy 
 secretase blockers
 relief of oxidative stress
 Apolipoprotein therapy
 stem cells for replacement
 vaccination 
 ginko biloba
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
Cholinergic therapy
 Cholinesterase inhibitors – delay symptoms
 Tacrine: allosteric – 1993 (toxic in liver)
 Donepezil; mixed binding
Try Cholinergic agonist
 M2 on basal ganglia and intestine
 Depletion of M1 receptors?
 M1 and M3 receptors in hippocampus
 Drug
trials discontinued
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!