20. Molecular pathogenesis of AD Flashcards

1
Q

Milestones in history of AD

A

1906 - first documentation (patient: Auguste D.) revealed amyloid between neurons & tangled bundles of fibrils in neurons (NFT)

1910-1940 - belief that “senile dementia” is normal aging process

1960s - AD believed to be distinct disease

1984 - amyloid beta peptide purified & sequenced from AD plaques

1992 - amyloid cascade hypothesis developed

1994 - oxidative stress is important feature of AD, role of metals in amyloid plaque formation

1998 - amyloid oligomers shown to be > important to memory impairment than amyloid plaques

2000 onwards - development of drugs to target amyloid generation/its removal (clinical trials)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Facts & figures of AD

A

35.6 mill patients in world (>500,000 in AUS)

Estimated 114 mill. patients by 2050 as world’s popn rapidly ages

Current worldwide cost to healthcare = US$604 billion/yr

Chance of getting AD doubles every 5 yrs after 65yo.
1/4 chance over 80yo.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the general neuropathy of AD?

A
  • gross atrophy od brain
  • extracellular neuritic (amyloid) plaques
  • intraneuronal NFT
  • cerebrovascular amyloid angiopathy (CAA)
  • activation of microglia
  • hypertrophy of astrocytes
  • degree of dementia/memory impairment in AD correlates with loss of synapses
  • loss of neurons as disease progresses
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are amyloid plaques?

A
  • aggregated amyloid beta peptide (forming fibrils)
  • green-red birefringence with congo red stain
  • many non-amyloid beta components in plaques
  • high [metal ions]
  • readily turned over in brain
  • may be ‘end point’ of amyloid pathway
  • assoc. with 2’ inflammation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is amyloid and what does amyloidogenic mean?

A

= starch/cellulose, has a rich beta sheet protein structure

*Amyloidogenic = protein aggregates appear red microscopically in normal light & green under polarising light after congo red dye staining (birefringence)

Amyloid are distinct from amorphous protein aggregates

1959 - Fibrillar nature & beta pleated sheet configuration described by electron microscopy.
*form non-branching fibrils of up to 8mm diameter.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe amyloid plaque formation.

A
  • amyloid formation is non specific for a primary protein sequence
  • amyloidogenic proteins can begin as unstructured monomers (little α-helix or β-sheet structure)
  • with increasing [ ], or under certain env. conditions, β-sheet structure increases
  • monomers begin to form parallel β-sheet structure (protofibril)
  • Protofibrils mature into fibrils & form plaques
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Oligomeric vs fibrillar Aβ

A

Monomeric Aβ peptide can:

  • aggregate to form fibrillar amyloid (insoluble)
  • form oligomeric (soluble) species consisting of 2-10+ monomers packed closely together called oligomers

Oligomers

  • may become cross linked by specific aa modifications (eg. di-tyrosine cross-link) increasing its stability
  • are thought to be primary toxic form of Aβ
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

How do you get amyloid β peptide?

A

Amyloid β is hydrophobic 40-42 aa peptide

It is cleaved from larger APP by secretases (BACE/β-secretase or γ-secretase).
*However APP can also be cleaved by α-secretase at a different site which prevents Aβ formation.

  • cleavage occurs at membrane of brain grey matter neurons, especially cerebral cortex & hippocampus
  • Aβ is released into extracellular space
  • but can be recycled back into cell by endocytosis
  • amyloid deposits form between cells (extracellular - brain parenchyma)
  • remaining APP released as soluble APP.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Describe the APP.

A

Integral memb protein concentrated at brain synaptic connections

Gene located on c’some 21.
In Down’s Syndrome (extra c’some 21), you overproduce APP & Aβ

Has domains w different functions:

  • growth factor-like domain
  • protease inhibitor domain
  • metal binding domains

APP undergoes extensive post-translational processing (phosph., glycosylation, cleavage)

Unknown function but inv in:

  • growth promotion
  • regulation of synaptic function
  • metal homeostasis
  • cell signalling
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the rate of amyloid turnover?

A

~8% of total CSF amyloid is turned over every 36 hours.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the process of amyloid turnover?

A

Proteases in the brain degrade amyloid peptide leading to its clearance.

  • insulin degrading enzyme
  • neprilysin
  • matrix metalloproteases
  • angiotensin converting enzyme

Microglia can also remove, especially aggregated peptide & plaques

AD brain has reduced clearance

~2% diff between prod rate & clr rate in AD patients may result in accumulation (potential therapeutic treatment to shift balance)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the normal function & dysfunction of amyloid?

A

Function:

  • antioxidant molecule (monomeric form)
  • modulating metal homeostasis (Cu, Zn)

Dysfunction:

  • aggregation into amyloid
  • aggregation in oligomers
  • neurotoxic effects
  • inflammation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly