BIOM30002 Lecture Notes - Lecture 34: Mild Cognitive Impairment, Neurofibrillary Tangle, Amyloid
12 Jun 2018
School
Department
Course
Professor
L34 Alzheimer’s Disease: clinical/molecular 1
AD
- Most common cause of dementia
- Symptoms: forgetful and transformation of personality
- Associated with aging
- ¼ people >85 age have dementia
- Incidence: F>M
- MMSE: mini mental state exam
- Clock drawing test
Natural progression of AD – prodromal AD and mild cognitive impairment (MCI)
- Pre-clinical
- Impairment in memory
- NCI
- Pathology: significant loss of neuron (= all age-related ND)
Pathological hallmarks of AD – protein deposits (2)
- Intracellular: NFT (neurofibrillary tangles) due to deposition of hyperphosphorylated tau
- Extracellular: Amyloid plaque due to deposition of Abeta peptide
Tau
- Part of cytoskeleton
1. interacts with tubulin to stabilize microtubule
2. regulate axonal transport of protein
- Mainly present in axons
- Microtubule binding repeats (R1-4)
- Function
1. Affects the transport of motor proteins (dynein and kinesin) along microtubules
2. Bind to mitochondria and modulate the interaction b/w microtubules and
mitochondria
- Mutated tau = hyperphosphorylation released from microtubule
1. Destabilise of tau-microtubule non-function neuron
2. Truncation impaired degradation?
3. Aggregation NFT formation
Tau isoforms
- Alternative splicing of tau gives various isoforms with different MW
- Tauopathies: driven by tau protein primarily
- Hyperphosphorylated tau aggregate tauopathy (disease-causing)
- Disease: change in
1. Metabolism of hyperphosphorylation site/state
2. Alternative splicing isoforms
3. Solubility
Kinases and tau phosphorylation
- Homeostasis of tau: kinase/phosphatase balance
- A-beta binds to
1. Ca2+ channels
2. Tyrosine kinase receptors
3. Other receptors
- Signal cascades (kinase/phosphatase)
- Responses:
1. Increased tau phosphorylation
2. NFT
3. Neuronal loss
Document Summary
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