20. Molecular pathogenesis of AD Flashcards
Milestones in history of AD
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)
Facts & figures of AD
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.
What is the general neuropathy of AD?
- 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
What are amyloid plaques?
- 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
What is amyloid and what does amyloidogenic mean?
= 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.
Describe amyloid plaque formation.
- 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
Oligomeric vs fibrillar Aβ
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 do you get amyloid β peptide?
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.
Describe the APP.
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
What is the rate of amyloid turnover?
~8% of total CSF amyloid is turned over every 36 hours.
What is the process of amyloid turnover?
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)
What is the normal function & dysfunction of amyloid?
Function:
- antioxidant molecule (monomeric form)
- modulating metal homeostasis (Cu, Zn)
Dysfunction:
- aggregation into amyloid
- aggregation in oligomers
- neurotoxic effects
- inflammation
