Molecular neurobiology of disease

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Transcript Molecular neurobiology of disease

Alzheimer’s disease
Alzheimer’s symptoms
genetic basis of early onset AD
amyloid hypothesis
Dementia – economic costs
 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
 ~5 years from MCI to diagnosis by physician
survival depends on age
@70 ~ 8 years
 @90 ~ 3 years
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
 ?preceded by MCI (mild cognitive impairment)
less movement
storage of new memory reduced
finally loss of bodily function
First: what happens to the brain in AD ?
 cortex very reduced
 cortex reduced - note gaps between folds
NL : normal
MCI: mild cognitive impairment
PET scan
loss of energy metabolism: hippocampal hypometabolism
predicts cognitive decline from normal aging
Cellular changes
AD brains feature
(Ab =
Next: tau
Neurofibrillary tangles
 micrograph
drawing by Alois Alzheimer
Development of tau
tau hypothesis
tau and microtubules
T : taxol binding
Although tau gets in way of cargo
transport, tau is required for MT
integrity. Normal equilibrium of
unbound tau-P and tau (bound)
Phosphorylation of tau
 tau-P mutations lead to
 these mutations more
readily phosphorylated
 kinases:
glycogen synthase kinase 3
 cyclin-dependent kinase 5
 microtubule-affinity-regulating
kinase (MARK)
Amyloid hypothesis
 Down’s syndrome leads to AD by 40
linked to chromosome 21
 Positional cloning identified:
mutations in bAPP (amyloid precursor protein)
670 / 692 / 716 & 717
amyloid-b (Ab) peptide 40-42 amino acids
 amyloid b toxic to cultures
 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
 code for two secretases b and g
 involved in processing bAPP
a secretase now called ADAM
b secretase called BACE
 BACE knockout mice rescue mouse model of AD
Proteolysis of APP
Where does BACE act ?
Promote a cleavage
 treat with BACE1
inhibitor localised to
 flies expressing APP /
presenilins (%eclosing)
 mice with inhibitor,
membrane localised
inhibitor (Ab level)
 therapy ????
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
 maybe normally degraded quickly
half life 1-2 hr in mice 8hr in human
 plaques resistant to degradation
 enzymes:
neprilysin & insulin-degrading-enzyme
 Neprilysin knockout mice
have more Ab42
Summary so far
 AD is disease of older people
early onset
 linked to Ab
 presenilins
 linked to tau
 Major problem : how does faulty b-amyloid lead to
tangles of tau?
Aβ impairs MT transport – needs tau
Do tau and Ab form complexes?
 form soluble complex which then precipitates?
 GSK-3 phosphorylates tau in complex
Ab is extracellular?
in neurons
lower magn.
Aβ oligomers induce missorting of Tau
Aβ Oligomers
yellow colour indicates tau in dendrites
Summary so far
 AD is disease of older people
early onset
 linked to Ab
 presenilins
 linked to tau
 tau and Ab ????
 Next: another genetic risk factor!
Apolipoprotein E
 Another family gene for late onset of AD produces
Apolipoprotein E
Apolipoprotein E - cont
 299 aa protein
secreted by astrocytes
and microglia
 Interacts with
receptors in the lowdensity lipoprotein
receptor family
 LRP1 expressed in
 LDLR in astrocytes
 normal role of ApoE is
in cholesterol
 may aid in clearance
of b-amyloid from
brain to blood
HSPG: heparin sulfate proteoglycan
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
Environmental factors
 Cold sores 'an Alzheimer's risk'
Therapy ??
cholinergic therapy 
NMDA block (Memantine) 
secretase blockers
relief of oxidative stress
Apolipoprotein therapy
stem cells for replacement
vaccination 
ginko biloba
see for review
 trial halted (2002) meningoencephalitis
follow up (2008) showed Ab clearance, but no
cognitive effect
 new vaccine(s) 2010 ?
29th July 2008
“drug works by
dissolving the tangle of
tau fibres”
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 (aricept); mixed binding
 Rivastigmine: low interaction with other drugs
preferentially blocks form of ACh-esterase found in brain
 delays decrease in MCI ~ 2 years
Try Cholinergic agonist
 M2 on basal ganglia and intestine
 Depletion of M1 receptors?
 M1 and M3 receptors in hippocampus
Drug trials discontinued
Other therapies ?
 bapineuzumab, a monoclonal anti-amyloid
antibody (Phase III)
 tarenflurbil (modulates gamma secretase activity)
(terminated in Phase III)
 dimebon (antihistamine) – phase II very +, phase III
no effect
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 ?
MS – PD – AD – what have we learnt?
 Genetics provided major insight
 Despite short lifespan, animal models of
neurodegeneration remarkably successful
 Range of therapies under development
many disappointments
 some successes
 Still no major understanding of the cause(s)
 Happy Christmas & New Year