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Aim
Alzheimer’s symptoms neurodegeneration genetic basis of early onset AD amyloid hypothesis treatment
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)
Forgetfulness untidiness confusion less movement storage of new memory reduced finally loss of bodily function
First: what happens to the brain in AD ?
PET scan
hippocampus
cortex
loss of energy metabolism: hippocampal hypometabolism predicts cognitive decline from normal aging
NL : normalMCI: mild cognitive impairment
tau and microtubules
Although tau gets in way of cargo transport, tau is required for MT integrity. Normal equilibrium of unbound tau-P and tau (bound)
T : taxol binding
Phosphorylation of tau
tau-P mutations lead to neurodegeneration
these mutations more readily phosphorylated
kinases: glycogen synthase kinase 3
(GSK3), cyclin-dependent kinase 5 (
CDK5) microtubule-affinity-
regulating kinase (MARK)
Amyloid hypothesis
Down’s syndrome leads to AD by 40 linked to chromosome 21
Positional cloning identified: mutations in APP (amyloid precursor protein)
670 / 692 / 716 & 717 amyloid- (A) peptide 40-42 amino acids amyloid 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 A production
Presenilins
code for two secretases and involved in processing APP
BACE knockout mice rescue mouse model of AD
secretase now called ADAM secretase called BACE
Promote cleavage
treat with BACE1 inhibitor localised to membrane
flies expressing APP / presenilins (%eclosing)
mice with inhibitor, membrane localised inhibitor (A level)
therapy ????
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 in mice 8hr in human
plaques resistant to degradation enzymes:
neprilysin & insulin-degrading-enzyme
Summary so far
AD is disease of older people early onset
linked to A plaques presenilins
linked to tau tangles
Major problem : how does faulty -amyloid lead to tangles of tau?
Do tau and A form complexes?
form soluble complex which then precipitates?
GSK-3 phosphorylates tau in complex
tau A
Ais extracellular?
in neurons
mergelower magn.
merge
Summary so far
AD is disease of older people early onset
linked to A plaques presenilins
linked to tau tangles
tau and A Next: another genetic risk factor!
Apolipoprotein E - cont 299 aa protein
secreted by astrocytes and microglia
Interacts with receptors in the low-density lipoprotein receptor family LRP1 expressed
in neurons LDLR in
astrocytes normal role of ApoE
is in cholesterol transport
may aid in clearance of -amyloid from brain to blood
HSPG: heparin sulfate proteoglycan
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
Therapy ??
cholinergic therapy NMDA block (Memantine) secretase blockers relief of oxidative stress Apolipoprotein therapy stem cells for replacement vaccination ginko biloba
see http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=972 for review
Vaccination
trial halted (2002) meningoencephalitis follow up (2008) showed A clearance, but no
cognitive effect new vaccine(s) 2010 ?
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
Rivastigmine
Tacrine
Donepezil
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 ?
!