PHAR30080 L15 RH principles of neurodegen diseases

learning outcomes

neurodegenerative diseases

• heterogenous group of neurological disorders adversely affecting the lives of millions of people worldwide

• progressive and irreversible loss of vulnerable population of neurons

• collapse of the structure and function of neural networks and loss of neurons

• breakdown of the core communicative circuitry

• no cure

neurodegen disease classification

• amyloidoses

• tauopathies

• synucleinopathies

• TDP-43 proteinopathies

cellular/anatomical distribution

table: correlation between aggregates and disease

brain regions, genetics and aggregating prots image

pathological hallmarks of ND diseases image

pathological protein aggregation image

biomarkers for NDD protein aggregation

• magnitude of cortical atrophy correlated with tau/amyloid burden

• evidence that magnitude of tau burden act as a valid marker for clinical symptoms and ND in AD

• development of disease-modifying therapies

protein misfolding as a principle mechanism

= misfolding protein PrPc → cause/driver of prion’s pathology

excitotoxicity

• neurotoxic effects due to excessive Glut

• results in neuronal cell death caused by excessive activation of Glut receptors (NMDA), leading to a harmful influx of Ca2+ → Ca2+ overload

excitotoxicity image

mechanisms of excitotoxicity image

Step 1. mechanisms of excitotoxicity

• Glut activates both NMDA, AMPA and metabotropic receptors

• activation of AMPA depolarises the cell → removes Mg2+ block on NMDA → Ca2+ entry

Step 2. mechanisms of excitotoxicity

• depolarisation → voltage-dependent Ca2+ channels

Step 3. mechanisms of excitotoxicity

• NMDA receptors: release of intracellular Ca2+ from ER, stimulation of Na+/Ca2+ exchange → further Ca2+ entry

Steps 4. mechanisms of excitotoxicity

• depolarisation inhibits or reverses Glut reuptake → increase in EC Glut

Step 5. mechanisms of excitotoxicity

• mechanisms that normally counteract increase of IC Ca2+ levels (Ca2+ efflux pump, Na+ pump)