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THE POSSIBILITY OF A DEMENTIA-FREE FUTURE: FANTASY OR REALITY?

THE POSSIBILITY OF A DEMENTIA-FREE FUTURE: FANTASY OR REALITY?. 3. 2. 1. Developing a Mind…. Newborn 3months 15months 2years. Connections Give Ever Deeper MEANING over time….

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THE POSSIBILITY OF A DEMENTIA-FREE FUTURE: FANTASY OR REALITY?

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  1. THE POSSIBILITY OF A DEMENTIA-FREE FUTURE: FANTASY OR REALITY?

  2. 3 2 1

  3. Developing a Mind… Newborn 3months 15months 2years

  4. Connections Give Ever Deeper MEANING over time…

  5. THE BIOLOGICAL BASIS OF THE MIND IS THE PERSONALISATION OF THE BRAINTHROUGH UNIQUE DYNAMIC CONFIGURATIONS OF NEURONAL CONNECTIONS, DRIVEN BY UNIQUE EXPERIENCES

  6. Developing And Losing One’s Mind… …Reflected In Brain Cell Branching (Connections)

  7. CURRENT APPROACHES

  8. INVASIVE APPROACHES CURRENT APPROACHES

  9. NON-INVASIVE APPROACHES INVASIVE APPROACHES CURRENT APPROACHES

  10. NON-INVASIVE APPROACHES INVASIVE APPROACHES THE ‘ANTICIPATORY’APPROACH CURRENT APPROACHES

  11. THE ANTICIPATORY APPROACH But degeneration can start 20-30 years before the onset of visible symptoms!

  12. (A) Marker for in blood detects degeneration before symptoms appear + (B) Medication for arresting further neuronal death = PERMANENT PREVENTION OF SYMPTOM ONSET! AN EVENTUAL ‘CURE’?

  13. What is the Basic Mechanism of Neurodegeneration?

  14. In search of the Basic Mechanism of Neurodegeneration Clue 1: Co-pathology: Alzheimer's, Parkinson’s, and ALS

  15. ‘Global Neurons’

  16. ‘SERIAL VS GLOBAL’ NEURONS (Woolf, 1996) • SERIAL • Primary sensory, relays, cerebellum, thalamus, hippocampus, cortex • Amino acids • Alar plate • Electrically silent • Lose plasticity • Insensitive to trophic factors • GLOBAL • Locus C., Raphe N., A9, A10, basal forebrain motorneurons • Ach, DA, NA, 5-HT • Basal plate • Spontaneously active • Robust plasticity • Sensitive to trophic factors

  17. ‘SERIAL VS GLOBAL’ NEURONS (Woolf, 1996) • SERIAL • Primary sensory, relays, cerebellum, thalamus, hippocampus, cortex • Amino acids • Alar plate • Electrically silent • Lose plasticity • Insensitive to trophic factors • GLOBAL • Locus C., Raphe N., A9, A10, basal forebrain motorneurons • Ach, DA, NA, 5-HT • Basal plate • Spontaneously active • Robust plasticity • Sensitive to trophic factors

  18. The ‘Isodendritic Core’: Rossor 1981 Cholinergic Striatal Interneurons Cholinergic Basal Forebrain Histamine Hypothalamus Serotonergic Raphe Dopaminergic Substantia Nigra Cholinergic Motor Neurons Cholinergic Pontomesencephalon Noradrenergic Cerulear Region Woolf 1996

  19. THE LOCUS COERULEUS Degree of cell death correlates with disease duration (Albanese & Butcher 1980) NORADRENALINE ACETYLCHOLINESTERASE (AChE) Demonstration in rostral locus cernleus of norepinephrine (A) and acetylcholinesterase (B) on the same brain section. Small arrows in A and B point to the same neuronal somata. Large arrow in B points to cell body in the mesencephalic nucleus of cranial nerve V. scale = 200mm

  20. In search of the Basic Mechanism of Neurodegeneration Clue 1: Co-pathology: Alzheimer's, Parkinson’s, and ALS Clue 2: Presence of key protein (AChE) in all Global neurons/Isodendritic core Clue 3: AChE is released

  21. Release of AChE from the SubstantiaNigra: (Llinás & Greenfield 1987)

  22. In search of the Basic Mechanism of Neurodegeneration Clue 1: Co-pathology: Alzheimer's, Parkinson’s, and ALS Clue 2: Presence of key protein (AChE) in all Global neurons/Isodendritic core Clue 3: AChE is released Clue 4: AChE promotes cell growth

  23. Trophic action of AChE in Hippocampus (Day & Greenfield 2002) Control AChE

  24. Trophic-Toxic Consequences of Increasing Levels of Calcium: (Dickie et al., 1996)

  25. Trophic or Toxic? Another Key Factor: AGE!

  26. Neurodegeneration: An Aberrant Form of Development Adult INSULT

  27. We have identified the molecular fragment of AChE that can operate independent of enzyme function: ‘AChE-Peptide’

  28. AChE C-Terminal Peptides

  29. Control AChE Peptide Administration of AChE-Peptide can be Toxic (Greenfield et al 2004)

  30. NEURODEGENERATION IS AN ABERRANT FORM OF DEVELOPMENT: AChE-PEPTIDE IS THE PIVOTAL TOXIC MOLECULE Biomarker In Vitro and In Vivo Models Therapeutic Intervention

  31. NEURODEGENERATION IS AN ABERRANT FORM OF DEVELOPMENT: AChE-PEPTIDE IS THE PIVOTAL TOXIC MOLECULE Biomarker

  32. Discovery of Biomarkers: Mass Spectrometry

  33. The AD-index: Higher AD-index at the early stage of the disease 83% of the values are above the median of the control 50% of the values are above the upper quartile of the control AD-index Time after diagnosis (years) 60 samples (30 AD and 30 control) R2 = 0.1297; P = 0.0040

  34. NEXT STEPS • Establish the relationship between the AChE-peptide and the current biomarker peptides • Identify the proteases involved in the cleavage of AChE, and subsequent metabolites of AChE-peptide in current samples • Determine how early the AD-index can diagnose Alzheimer’s disease • Confirm the specificity of this index (comparison with non-neurodegenerative disorders) • Produce a diagnostic feature for Alzheimer’s disease (ELISA kit, etc.)

  35. NEURODEGENERATION IS AN ABERRANT FORM OF DEVELOPMENT: AChE-PEPTIDE IS THE PIVOTAL TOXIC MOLECULE Biomarker In Vitro and In Vivo Models

  36. (A) CHROMAFFIN/PC12 CELLS:

  37. (A) CHROMAFFIN/PC12 CELLS: (1) Lewy body inclusions (Averback 1983)(2) Neurofibrilliary tangles & paired helical filaments: (Izumiyama et al., 1990)(3) Expression of APP (Takeda et al., 1994)(4) Aberrant secretion of AChE(Appleyard & MacDonald 1991)(5) A ‘window on the brain’ (Bornstein et al., 2012)

  38. AChE-Peptide (T30) is Toxic in PC12 cells.... 30 % Reduction on Cell Viability (1 h)

  39. A Specific Compensatory Response?

  40. Could A and T30 peptide share a final common path of action?

  41. Synergy of A and T30 peptide after 1 hour AChE activity in perfusate Cell viability

  42. (A) CHROMAFFIN/PC12 CELLS: Advantages: Highly reductionist Easy and quick to culture Implicated already in AD Release AChEDisadvantages: Not brain cells

  43. (B) OPTICAL IMAGING: BRAIN SLICES

  44. Badin et al., 2013

  45. Advantages: Brain cells Functional circuitry retained (>10m cells) Time resolution of action potentials Differential spatial and temporal dynamics Disadvantages: In Vitro (B) OPTICAL IMAGING: BRAIN SLICES

  46. (C) IN VIVO RAT

  47. The Cylinder Test: Sensitive indicator of neurological damage (Schallert, 2000)

  48. GFAP IR IN THE BASAL FOREBRAIN 7 days post treatment Control T30 1μM T30 100μM

  49. Advantages: Functional effects Histological effects Disadvantages: Indirect action Basic mechanism not revealed (C) IN VIVO RAT

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