lecture VI-VII: Alzheimer's Flashcards
Dementia
General term describing impairment of memory and cognitive functions.
Alzheimer’s disease
Specific form of dementia and includes pre-symptomatic stages.
→progressive neurodegenerative disorder
→impairment of cognitive functions, spatial orientation, memory, language, change of personality
Alzheimer disease progression
- Healthy brain
→gradual cognitive decline
→no obvious brain pathology - Pre-clinical
→cognitive decline in episodic memory
→no obvious brain pathology - MCI
→accelerated cognitive decline
→observable brain pathology - AD
→severe dementia
→loss of life independence
→severe loss of brain tissue
Pathological hallmarks of AD
- Amyloid plaques
→A-beta peptides - Lipid accumulation
- Neurofibrillary tangles
→hyperphosphorylated tau protein
Pathological hallmarks of AD: Macroscopic level
Evident neurodegeneration
→atrophy
→massive neuronal loss
Which of the pathological hallmarks is not specific to AD?
Hyperphosphorylated tau proteins.
→also found in other forms of dementia
If you were Alois Alzheimer, what would you like to know next?
- Are there other AD patients with similar amyloid plaques?
- Are amyloid plaques linked to dementia?
- Is there a correlation between the amount of amyloid plaques and the degree of dementia? (i.e. target validation)
A-beta generation: steps + draw it!
- Amyloid precursor protein (APP) is cleaved by beta-secretase into CTF-beta
- sAPP-beta is released
- gamma-secretase complex is recruited
- CTF-beta is cleaved by gamma-secretase
- Amyloid-beta is released in the extracellular space
- AICD remains in the intracellular space
APP
Amyloid precursor protein.
→type I transmembrane protein
→expressed in brain neurons, but also in other parts of the body (i.e. liver, muscle)
When does APP become a substrate for gamma-secretase?
Only once shedding has occurred.
APP shedding
The process by which membrane-bound proteins undergo proteolytic release from the membrane.
In this case, it is when sAPP-beta is released APP (resulting in CTF-beta) through the action of beta-secretase proteolytic cleavage
T or F: A-beta peptides all have the same size.
False!
Their size depends on how much is cleaved off by gamma-secretase
Which A-beta peptide size is most commonly seen in amyloid plaques?
A-beta 42.
→A-beta 42 is more likely to aggregate to form plaques in the brain
T or F: Sporadic AD cases are most common.
True!
They consist of 97% of cases, whereas dominant inherited familial AD cases only consist of 3%.
Presenilins
A family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex.
→presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP
Familial AD mutations
Low frequency, high penetrance
→ carriers of such mutations will get AD
A-beta oligomers
A hypothesis proposes that the brain damage leading to AD was instigated by soluble, ligand-like AβOs
→inhibit long term potentiation
→neurotoxic
Amyloid hypothesis
A-beta is toxic and causes death of neurons, leading to AD.
- APP located on chromosome 21
→Trisomy 21: AD with 40 years for DS patients - Hereditary, familial AD mutations causing early onset AD in APP and Presenilin
- Increased A-beta levels in sporadic and familial forms of AD
→due to reduced A-beta clearance in sporadic AD cases - Icelandic mutation A673T protects from AD and produces less A-beta
T or F: The amyloid hypothesis is absolute.
False!
There is a poor correlation between plaque load and cognitive function
A-beta toxicity
- soluble oligomers of A-beta are most toxic and impair memory the most
- not identified by mass spectrometry
- structure unclear, chewing gum
→amyloid plaques are rather an effective defence mechanism for the detoxification of oligomers
AT(N) system
Assesses AD progression based on these 3 characteristics:
- A+ : amyloid
- T+ : tau
- N+ : neurodegeneration
→people must have both A & T to be characterized as AD
Available treatments for AD
Only symptomatic treatments available with modest benefits:
- Cholinesterase inhibitors
- NMDA receptor antagonists
- Aducanumab
Mechanisms for pharmacological intervention of AD
- Decrease A-beta production
- Decrease A-beta aggregation
- Increase A-beta clearance
- Decrease tau aggregation or phosphorylation
- cholinergic drugs
Considerations before a drug screen: A-beta edition
☆lecture 7 - slide 9☆
Amyloid hypothesis arguments against
- There are 210-250 other genes on chromosome 21 (correlation)
- Mutations causatively link APP and PS, not A-beta (correlation)
→PS has 150 substrates - Not all FAD mutations increase A-beta 42, absolute A-beta levels vary by a lot
→Sporadic AD: decreased Ab clearance
→Familial AD: increased Ab production - Mutations causatively link APP, not A-beta (correlation)
- Quasi impossible to prove in vivo, only in vitro
Mendelian inherited, dominant disease-causing mutations in AD
- Presenilin 1 and 2
- APP
Physiological function of APP
- transcription
→AICD is shown to be transcriptionally active - synaptic plasticity
- cell-cell / cell-matrix interactions
- cell survival / neuroprotection
- axonal outgrowth
APP locations
Subcellular: ER, Golgi, endosomes
What could it possible help to know APP’s physiological function?
- reveal if A-beta is formed when APP executes its function or not
- assess if FAD mutations in APP are loss or gain-of-function
- reveal the underlying biology of dysfunction in AD
→which cellular pathways lead to dysfunction of APP, and then in consequence to Ab production? - develop an assay for APP functionality
- assess existing treatments and interventions in light of APP function
Biased research approach
- follow a hypothesis
- make informed decisions
- integration of existing literature
Unbiased research approach
- powerful through high sample number, statistical significance
- not driven by one specific hypothesis, but creating new hypothesis
Unbiased research approach: methods
- Proteomics, Metabolomics, Lipidomics, Genomics, Transcriptomics, Epigenomics, Multiomics
- GWAS
- RNAseq
- Screens – drug libraries, CRISPR screens
- Reverse Phase Protein Array (RPPA), O-link
