Alzheimer’s disease

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 ?

Neuroanatomy

cortex very reducednormal Alzheimer

Neuroanatomy

cortex reduced - note gaps between folds

PET scan

hippocampus

cortex

loss of energy metabolism: hippocampal hypometabolism predicts cognitive decline from normal aging

NL : normalMCI: mild cognitive impairment

Cellular changes

AD brains feature plaques

(A =-amyloid)

tangles(tau)

Next: tau

Neurofibrillary tangles

micrograph drawing by Alois Alzheimer

Development of tau

tau hypothesis

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

Proteolysis of APP

Normal AD

Where does BACE act ?

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

Neprilysin

Neprilysin knockout mice have more A

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?

Aβ impairs MT transport – needs 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

Aβ oligomers induce missorting of Tau

yellow colour indicates tau in dendrites

Aβ Oligomerscontrol

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

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 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

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 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 ?

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

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 ?

!

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