Ageing Brain

Ageing Brain

1. Why ageing?

   • 150,000 people die each day
   • Patridge (2014): comorbid with CVD, Dementia, Diabetes
   • Caloric restriction: McCay et al. (1935) increase in lifespan related to reduction of calorie intake
     • Nutrient- sensing pathways implicated (3)
       • Partridge (2014): reducing IIS & TOR activity increases lifespan and health in variety of species
       • Cohen (2009): reducing IIS activity in a mouse model of Alzheimers = reduced behaviour and biomarkers
     • Partridge (2010) found similar result in primates
   • Three definitions of ageing: senescence, cellular, organismal

2. Biology of Ageing

   • Cellular Senescence (Hayflick Limit)
     • Shortening of telomeres with each cell cycle
     • Telomerase maintains the length of telomere in immortal cells
     • Telomerase gene usually switched off
     • Ornish et al. (2013): lifestyle changes can increase telomere length in cancer patients

3. Early Embryonic Development

   • Zygote, Cleavage, Blastomere, Morula, Blastocyst, Blastula, Gastrulation
     • Ectoderm: skin and tissue -receives signals from mesoderm
       • Mesoderm: connective tissue, skeleton, cardiac tissue
         • Endoderm: digestive and respiratory system

4. Neural Tube Development

   • Interior: cerebral ventricles and spinal canal
     • 40 days: top of tube thickens to hindbrain, midbrain, forebrain
     • Ridges fuse to form the neural tube
       • Uneven rate of division = ridges = neural groove
         • Ectoderm builds up forming neural plate (3-4)
           • Embryonic Stem cells (pluripotent)
             • Kitada and Dazawa (2012): Parkinsons' Disease: protect tissue damage, generate into dopamine neurons
             • Yamasaki et al. (2007): Alzheimer; survive, migrate, differentiate, improve memory

5. Neural Proliferation

   • Cells of the neural tube divide rapidly mainly in ventricular zone

6. Migration

   • Radial or tangential migration
   • Radial cells used as a ladder (Herrup & Stuer, 1994)
   • Inside-first, outside-last layering
   • Subventricular zone (between intermediate and ventricular) = glial or inter-neurones
   • Neruonal Migration Disorder: seizure, LD

7. Aggregation

   • Align with other neurones to form structures
   • Guided by Cell-Adhesion molecules (CAMs)- Fazeli & Walsh (1996)

8. Axon Growth and Synapse Formation

   • Chemoaffinity
   • Topographic gradient
   • Blueprint

9. Neurone Death

   • 50% more produced than survive (NGF)
   • Necrosis: passive, spill, inflammation
   • Apoptosis: active, cleaved
     • Inhibition: cancer
     • Activation: neurodegenerative disorder
   • Synapse re-arrangement: tuned to connect to small number of cells = refines neural circuits

10. Cell Proliferation

    • Neural plate: notochord, roof and floor plate of mesoderm (Dodd et al., 1998)
      • Transcription factors: bind to DNA sequences (on/off)
        • Gene regulation: structural/fucntional characteristics
          • Wnt and Sonic Hedgehog are TF in mesoderm (Ulloa & Marti, 2009)
            • Further away from mesoderm = lower conc. of TF
              • Gradient and regional differences = become different structures