1 / 41

Alzheimer’s disease

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

azura
Download Presentation

Alzheimer’s disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Alzheimer’s disease

  2. Aim • Alzheimer’s symptoms • neurodegeneration • genetic basis of early onset AD • amyloid hypothesis • treatment

  3. 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

  4. 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,

  5. 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 ?

  6. Neuroanatomy • cortex very reduced normal Alzheimer

  7. Neuroanatomy • cortex reduced - note gaps between folds

  8. NL : normal MCI: mild cognitive impairment PET scan hippocampus cortex loss of energy metabolism: hippocampal hypometabolism predicts cognitive decline from normal aging

  9. Cellular changes AD brains feature • plaques(Ab =b-amyloid) • tangles(tau) Next: tau

  10. Neurofibrillary tangles • micrograph drawing by Alois Alzheimer

  11. Development of tau

  12. tau hypothesis

  13. 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)

  14. 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) Phosphorylation of tau

  15. 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

  16. 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

  17. Presenilins • code for two secretases b and g • involved in processing bAPP • BACE knockout mice rescue mouse model of AD a secretase now called ADAMb secretase called BACE g b a

  18. Proteolysis of APP AD Normal

  19. Where does BACE act ?

  20. treat with BACE1 inhibitor localised to membrane flies expressing APP / presenilins (%eclosing) mice with inhibitor, membrane localised inhibitor (Ab level) therapy ???? Promote a cleavage

  21. 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 in mice 8hr in human • plaques resistant to degradation • enzymes: • neprilysin & insulin-degrading-enzyme

  22. Neprilysin • Neprilysin knockout mice have more Ab42

  23. Summary so far • AD is disease of older people • early onset • linked to Ab • plaques • presenilins • linked to tau • tangles • Major problem : how does faulty b-amyloid lead to tangles of tau?

  24. Aβ impairs MT transport – needs tau

  25. Do tau and Ab form complexes? • form soluble complex which then precipitates? • GSK-3 phosphorylates tau in complex Ab is extracellular? lower magn. merge tau Ab merge in neurons

  26. Aβ oligomers induce missorting of Tau control Aβ Oligomers yellow colour indicates tau in dendrites

  27. Summary so far • AD is disease of older people • early onset • linked to Ab • plaques • presenilins • linked to tau • tangles • tau and Ab ???? • Next: another genetic risk factor!

  28. Apolipoprotein E • Another family gene for late onset of AD produces Apolipoprotein E

  29. 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 b-amyloid from brain to blood HSPG:heparin sulfate proteoglycan 

  30. 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

  31. Environmental factors • Cold sores 'an Alzheimer's risk'

  32. 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

  33. trial halted (2002) meningoencephalitis follow up (2008) showed Ab clearance, but no cognitive effect new vaccine(s) 2010 ? Vaccination

  34. 29th July 2008 “drug works by dissolving the tangle of tau fibres”

  35. 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

  36. 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 Tacrine Rivastigmine Donepezil

  37. Try Cholinergic agonist • M2 on basal ganglia and intestine • Depletion of M1 receptors? • M1 and M3 receptors in hippocampus • Drug trials discontinued

  38. 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

  39. 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 ? • !

  40. 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

More Related