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PHAR 503 > lecture VI-VII: Alzheimer's > Flashcards

lecture VI-VII: Alzheimer's Flashcards

1
Q

Dementia

A

General term describing impairment of memory and cognitive functions.

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2
Q

Alzheimer’s disease

A

Specific form of dementia and includes pre-symptomatic stages.

→progressive neurodegenerative disorder
→impairment of cognitive functions, spatial orientation, memory, language, change of personality

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3
Q

Alzheimer disease progression

A
  1. Healthy brain
    →gradual cognitive decline
    →no obvious brain pathology
  2. Pre-clinical
    →cognitive decline in episodic memory
    →no obvious brain pathology
  3. MCI
    →accelerated cognitive decline
    →observable brain pathology
  4. AD
    →severe dementia
    →loss of life independence
    →severe loss of brain tissue
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4
Q

Pathological hallmarks of AD

A
  1. Amyloid plaques
    →A-beta peptides
  2. Lipid accumulation
  3. Neurofibrillary tangles
    →hyperphosphorylated tau protein
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5
Q

Pathological hallmarks of AD: Macroscopic level

A

Evident neurodegeneration

→atrophy
→massive neuronal loss

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6
Q

Which of the pathological hallmarks is not specific to AD?

A

Hyperphosphorylated tau proteins.
→also found in other forms of dementia

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7
Q

If you were Alois Alzheimer, what would you like to know next?

A
  1. Are there other AD patients with similar amyloid plaques?
  2. Are amyloid plaques linked to dementia?
  3. Is there a correlation between the amount of amyloid plaques and the degree of dementia? (i.e. target validation)
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8
Q

A-beta generation: steps + draw it!

A
  1. Amyloid precursor protein (APP) is cleaved by beta-secretase into CTF-beta
  2. sAPP-beta is released
  3. gamma-secretase complex is recruited
  4. CTF-beta is cleaved by gamma-secretase
  5. Amyloid-beta is released in the extracellular space
  6. AICD remains in the intracellular space
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9
Q

APP

A

Amyloid precursor protein.

→type I transmembrane protein
→expressed in brain neurons, but also in other parts of the body (i.e. liver, muscle)

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10
Q

When does APP become a substrate for gamma-secretase?

A

Only once shedding has occurred.

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11
Q

APP shedding

A

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

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12
Q

T or F: A-beta peptides all have the same size.

A

False!

Their size depends on how much is cleaved off by gamma-secretase

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13
Q

Which A-beta peptide size is most commonly seen in amyloid plaques?

A

A-beta 42.

→A-beta 42 is more likely to aggregate to form plaques in the brain

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14
Q

T or F: Sporadic AD cases are most common.

A

True!

They consist of 97% of cases, whereas dominant inherited familial AD cases only consist of 3%.

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15
Q

Presenilins

A

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

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16
Q

Familial AD mutations

A

Low frequency, high penetrance
→ carriers of such mutations will get AD

17
Q

A-beta oligomers

A

A hypothesis proposes that the brain damage leading to AD was instigated by soluble, ligand-like AβOs

→inhibit long term potentiation
→neurotoxic

18
Q

Amyloid hypothesis

A

A-beta is toxic and causes death of neurons, leading to AD.

  1. APP located on chromosome 21
    →Trisomy 21: AD with 40 years for DS patients
  2. Hereditary, familial AD mutations causing early onset AD in APP and Presenilin
  3. Increased A-beta levels in sporadic and familial forms of AD
    →due to reduced A-beta clearance in sporadic AD cases
  4. Icelandic mutation A673T protects from AD and produces less A-beta
19
Q

T or F: The amyloid hypothesis is absolute.

A

False!

There is a poor correlation between plaque load and cognitive function

20
Q

A-beta toxicity

A
  • 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

21
Q

AT(N) system

A

Assesses AD progression based on these 3 characteristics:

  1. A+ : amyloid
  2. T+ : tau
  3. N+ : neurodegeneration

→people must have both A & T to be characterized as AD

22
Q

Available treatments for AD

A

Only symptomatic treatments available with modest benefits:

  1. Cholinesterase inhibitors
  2. NMDA receptor antagonists
  3. Aducanumab
23
Q

Mechanisms for pharmacological intervention of AD

A
  1. Decrease A-beta production
  2. Decrease A-beta aggregation
  3. Increase A-beta clearance
  4. Decrease tau aggregation or phosphorylation
  5. cholinergic drugs
24
Q

Considerations before a drug screen: A-beta edition

A

☆lecture 7 - slide 9☆

25
Q

Amyloid hypothesis arguments against

A
  1. There are 210-250 other genes on chromosome 21 (correlation)
  2. Mutations causatively link APP and PS, not A-beta (correlation)
    →PS has 150 substrates
  3. 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
  4. Mutations causatively link APP, not A-beta (correlation)
  5. Quasi impossible to prove in vivo, only in vitro
26
Q

Mendelian inherited, dominant disease-causing mutations in AD

A
  1. Presenilin 1 and 2
  2. APP
27
Q

Physiological function of APP

A
  1. transcription
    →AICD is shown to be transcriptionally active
  2. synaptic plasticity
  3. cell-cell / cell-matrix interactions
  4. cell survival / neuroprotection
  5. axonal outgrowth
28
Q

APP locations

A

Subcellular: ER, Golgi, endosomes

29
Q

What could it possible help to know APP’s physiological function?

A
  • 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
30
Q

Biased research approach

A
  • follow a hypothesis
  • make informed decisions
  • integration of existing literature
31
Q

Unbiased research approach

A
  • powerful through high sample number, statistical significance
  • not driven by one specific hypothesis, but creating new hypothesis
32
Q

Unbiased research approach: methods

A
  • Proteomics, Metabolomics, Lipidomics, Genomics, Transcriptomics, Epigenomics, Multiomics
  • GWAS
  • RNAseq
  • Screens – drug libraries, CRISPR screens
  • Reverse Phase Protein Array (RPPA), O-link

PHAR 503 (6 decks)

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