Alzheimer’s disease biology

Question 1

state some statistics around dementia

Answer 1

Dementia affects about 7% of the over 65s in the UK, this is a total of under 1 million patients at present, but will likely be over 2million by 2050.

Question 2

name some Characteristics of Alzheimer’s Disease

Answer 2

maller brain compared to matched controls
- Hippocampus - entorhinal cortex
- impairment of recent memory functions and memory
- Basal nucleus of Meynert - cholinergic system
- failure of language skills
- disorientation
- impaired judgement
- personality change

Question 3

name the Hallmarks

Answer 3

• neuritic plaques
  
  • extracellular lesion
  • made up of A-beta (amyloid)
• neurofibrillary tangle
  
  • intracellular lesion
  • made up of microtubule associated protein

Question 4

what is role of genes?

Answer 4

• APP gene on chr21
• ApoE on chr19
  
  • important in cholesterol metabolism
  • released by astrocytes for neuron damage repair

Question 5

what are some biomarkers?

Answer 5

• atrophy of medial temporal lobe on MRI brain scans (episodic memory)
• abnormal CSF biomarker - amyloid and tau
• autosomal dominant genetic mutation within family

Question 6

describe the pathology of AD

Answer 6

• Amyloid precursor protein (APP): repair and regeneration of nerve cells
  
  • broken down by secretases into beta-amyloid (Ab)
  • amyloid plaques due to Ab42 which is insoluble and toxic to neurons
  • deposition of Ab = disrupts normal functioning of brain
• Microtubules form skeleton the axon of neuron and help transport chemicals towards synapse for transmission
  -tau protein helps to stabilise neuronal cytoskeleton
  
  • destabilisation = form tangles
  • granulovacuolar degeneration - marker of previous damage

Question 7

What is p-tau

Answer 7

p-tau is a Microtubulue (MT) associated protein (supports cytoskeleton)

Question 8

what mechanisms could explain how Tau abnormalities affect neurones

Answer 8

• Q1) mechanisms of dysfunction of neurons
  
  • how does it affect circuit
• Q2) mechanisms of degeneration
  
  • neuronal loss
• Q3) What causes clinical symptoms
  
  • Drug targets?
    => abnormalities in tau → to tangles → neurodegeneration → clinical symptoms

Question 9

Why is Tau/tangle pathology Implicated in AD?

Answer 9

• mutations in tau gene DO NOT cause AD!
• mutations in tau cause Fronto-temporal dementia ch17
• tangle pathology only pathological entity in FTDP-17
  
  • abnormalities in tau → to tangles → neurodegeneration
• NOTHING ELSE NECESSARY
• other neurodegenerative diseases with prominent tangle pathology identified = TAUOPATHIES

Question 10

How is tau abnormal in AD and other tauopathies?

Answer 10

• neurofibrillary tangle
• in some AD: mutated in FTDP-17
• in all AD: hyperphosphorylated in all tauopathies
  
  • phosphorylation: controls protein function
  • hyper - 100 % of proteins
• abnormally expressed in FTD and AD?
• forms filaments in all tauopathies (Goedert, 1997)
  
  • aggregated

Question 11

How could these tau abnormalities cause neuronal dysfunction

Answer 11

1. Loss of normal physiological function
2. Gain of toxic function

Question 12

What does tau normally do in neurones?

Answer 12

• efficient axonal transport
• intact synaptic connectivity

Question 13

Can abnormal tau affect this?

Answer 13

• mutation, hyperphosphorylation, over expression, filament formation
  1. reduced binding to MT
  2. MT tracks collapse
  3. axonal transport compromised
  4. disruption of synaptic connectivity
  experimental evidence: by mudher et al.., 2004

Question 14

How can we counter abnormal tau mediated neuronal dysfunction?

Answer 14

• reduce tau phosphorylation: kinase inhibitors
  
  • but could inhibit kinases everywhere we only want to target one
    
    • low patient compliance due to severe side effects
• microtubule stabilising agents; NAP

Question 15

Testing tau-MT hypothesis

Answer 15

• p-tau
• if neuron ‘sick’ - target to improve axons!
• microtubule stabilising drugs
  
  • can NAP come to rescue?
    
    • cell division in cancer relies on MT
    • so MT stabilisation works - chemotherapy
    • synaptic defects; improved with NAP10
      
      • improved memory but not if neuron already dead
    • behavioural defects

Question 16

How could tau cause neurodegeneration?

Answer 16

toxic gain of function; abnormal protein

Question 17

by what mechanism could tau cause neurodegeneration?

Answer 17

• expression of mutant of phosphor-mimicking true in animal models causes neurodegeneration (ND)
• ND is aggregation dependant
• mechanism unclear but varies sugesstins include:
  
  • oxidative stress
  • apoptosis
  • necrosis
  • simple sauce occupying lesion
  • synaptic and nuclear deficits
  • speed competence
• spread of pathology

Question 18

what is the toxic species?

Answer 18

• tangle or smaller oligomeric species?
• tau misfolds → aggregates
• tangle; actively sequesters species-stays in one place to possibly prevent damage?
• smaller: intermediate species; smaller number of misfolded proteins come together
  
  • surface area to stop multiple oligomers greater than clumping together
  • more mobile and faster

Question 19

How does disease spread?

Answer 19

• Traditional view: Break Staging
• Current view: Cell-cell propagation

Question 20

describe Traditional view: Break Staging

Answer 20

• 900 subjects ranging in age from 25-90 years
• everybody had tau pathology
• disease spread reflect clinical symptoms
• there is stereotypical spread of pathology across connected brain regions
• stereotypical propagation of pathology through neural networks
• spreads due to neuroanatomical connections to region where pathology with major tangles appears
  
  • synaptic connection regions

Question 21

Current view: Cell-cell propagation

Answer 21

• in-vivo demonstration
  
  • 4R P301S (tau filaments) to 4R tau (no tau filaments)
  • tau converts other proteins into itself = seed competent
  • templated = faithful into turning other proteins into itself
    
    1. aggregated prone tau can induce aggregation of non-aggregate prone tau
    2. tau aggregates act in a prion-like manner
  • propagation of distinct conformational strains
    
    3. tau aggregates exhibit prion-like transynaptic transmission

Question 22

describe the seed spread analogy

Answer 22

• a seed is required for the spread of tau pathology
  
  • required tau - misfolded protein
    
    • what about cofactors that could cause AD?
  • can be induced by tau filaments and oligomers
  • acts in a prion-like templated fashion
  • 4R P301L expression restricted to EC
    
    • tau pathology spreads to anatomociallt linked regions
  • P301S homogenate IP injection into P301S mice
    
    • greater tau aggregates in IP animals
  • lenti viral P301L or wt tau injected in CA1
    
    • wt > P301L
    • de-P tau is spreading species

Question 23

what are the Outstanding questions?

Answer 23

• What is the transmissible tau species?
  
  • Does it have any special properties?
  • Is it misfolded/aggregated/phosphorylated?
• What is the pathological significance of transmission?
  
  • Does it occur in patients?
  • Does it matter?
• What are the synaptic mechanisms that underpin transmission?
• Can we devise therapies to inhibit transmission?
  
  • anti-oligomer antibodies
  • clearing tau oligomers
  • reducing tau phosphorylation

Question 24

summarise the Role played by tau/tangles in AD

Answer 24

• Tau protein is abnormal is hyper-phosphorylated, misfolded and aggregated in all tauopathies; it forms oligomres and tangles
• Q1: Hyper-phosphorylated tau causes neuronal dysfunction by disruption of cytoskeletal integrity leading to axonal transport and synaptic dysfunction
• Q2: Misfolded tau seeds (likely to be oligomers NOT NFTs) can propagate pathology across anatomically linked regions and cause neurodegeneration in prion-like manner
• Q3: Thus tau-centric therapies can counter 1 (e.g. kinase inhibitors, MT stabilising drugs) or 2 (anti-tau oligomer antibodies; agents that prevent spread, anti-oxidants etc).