Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BIOL354: Pathobiology > Lecture 1: Alzheimer's Disease > Flashcards

Lecture 1: Alzheimer's Disease Flashcards

1
Q

What is dementia?

A

A loss of cognitive function (neurodegeneration) associated with behavioural issues that interfere with daily activities

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

What is the most common form of dementia?

A

Alzheimer’s disease

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

What are the clinical features of Alzheimer’s disease?

A
  • Progressive loss of short term memory
  • Aphasia (loss of speech)
  • Apraxia (inability to make voluntary movements)
  • Agnosia (poor object recognition)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the non-modifiable risk factors of AD?

A

Age (exponential increase in risk as people get older - particularly over 80 - universal feature)

Sex (women may be more likely to develop AD)

Genetics (some cases due to mutations associated with familial AD)

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

What genetic mutations are associated with familial AD?

A

mutations in:
- amyloid precursor protein (APP)
- Presenilin 1 (PS1)
- Presenilin 2 (PS2)

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

_____ in more than ___ genes have been identified that are associated with sporadic AD?

A

SNPs in more than 30 genes have been identified that are associated with sporadic AD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

SNPs in which gene have shown particularly strong association with sporadic AD?

A

SNPs in APOE gene
- there are three different alleles of the APOE gene that an individual can inherit (APOE2, 3, or 4)
- Individuals with the APOE4 allele (wither one or two copies) have increased risk of developing sporadic AD and tend to develop it at an earlier age.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the modifiable risk factors of AD?

A
  • Metabolic and vascular risk factors - diabetes, hypertension, hypercholesterolaemia, obesity
  • diet and nutrition - high in sat fat, not enough folic acid, vitB12, vit B6
  • lifestyle factors - smoking, drinking, inactivity (evidence that links people who are more socially active, have higher mentally demanding jobs etc are at a lower risk of developing AD)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the key hallmarks of AD pathology

A

Key hallmarks
Extracellular senile plaques composed of beta amyloid protein
Intracellular neurofibrillary tangles composed of tau protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Other than NFTs and senile plaques, what other pathological features are associated with an AD brain?

A

reactive astrocytes - large cell bodies and thick processes

activated microglia -immune cells of the brain - aggregate around extracellular plaques - inflammation

synaptic dysfunction, neuronal death, ultimately brain shrinkage (due to fewer neurons)

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

True or false: Presence of senile plaques and NFTs are sufficient to diagnose AD?

A

False: the person must have them but they can also be present in other diseases so additional pathological features would be necessary to diagnose AD

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

What is beta-amyloid protein?

A

From processing of amyloid precursor protein and the beta-amyloid peptide is misfolded into two types/lengths:
- beta-40
- beta-42

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What stains are used to identify beta-amyloid and why?

A

Congo red or Thioflavin because they bind to beta sheets, which is high in the aggregated form of beta-amyloid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What causes beta-amyloid aggregates to be resistant to proteolysis?

A

They are dense aggregates with a high beta sheet content

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe the non-amyloidogenic pathway of amyloid precursor protein processing

A

TM APP expressed in neurons
- initial cleavage if APP by alpha-secretase in the middle of the amyloid-beta sequence to generate 2 fragments: a soluble APP-alpha fragment and a protein C83 - each containing a portion of the amyloid-beta sequence.
- gamma-secretase cleaves C83 and a small P3 fragment is generated and not prone to aggregation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Describe the amyloidogenic pathway of amyloid precursor protein processing

A

Beta-secretase cleaves at N-terminal end of the A-beta sequence resulting in a sAPP-beta fragment and a C99 protein that contains the entire amyloid-beta sequence.

gamma-secrete then cleaves A-beta sequence at C-terminal in C99 to produce a full 40/42 amino acid peptide A-beta protein that is prone to aggregation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Describe how Amyloid-Beta is believed to cause neurotoxicity

A

Amyloid-beta initially produced as 40/42 length peptide monomers
- monomers have high kinetic energy to favour aggregate and form oligomers and eventually fibrils
- the intermediate oligomer stage is believed to be the most toxic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How many APP mutations have been identified?

A

more than 50 - these mutations may affect whether APP is more likely to be cleaved by the beta or alpha secretase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Why may people with mutations in PS1 and/or PS2 be more more susceptible to AD?

A

Presenilin 1 and 2 are part of the gamma secretase protein complex so mutations in these proteins may affect the cleavage properties of the gamma secretase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

How does tau function in a normal neuron?

A

Microtubules within neuron maintain stability of axon by binding to phosphorylated tau

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What causes dysfunctional tau and what are the consequences of this?

A

Tau becomes hyperphosphorylated
consequences: dissociates from MT and aggregates, MT now unstable and fall apart = axon vulnerable to disruption, neuron starts to die

22
Q

What makes up NFTs?

A

Paired helical filaments (PHFs) - 10-20 nm filaments that wind together - pathological species that aggregate to form the NFTs when tau is hyperphosphorylated

23
Q

What is MAPT?

A

Microtubule associated protein tau

24
Q

How many major tau isoforms are there, how are they produced and how do they vary?

A

there are 6 tau isoforms formed by alternative splicing

one foetal tau and five adult tau isoforms

Contain a number of microtubule binding repeats (possibility of up to four repeat domains R1, R2, R3, R4) that contain phosphorylation sites.

25
Q

Which isoforms are present in the paired helical filaments (PHFs)?

A

All 6 isoforms and tau is 100% phosphorylated

26
Q

What is the equivalent of paired helical filaments in the formation of senile plaques?

A

Amyloid fibrils

27
Q

True or False: Mutations in MAPT are known to result in the development of AD?

A

False: no mutations in the MAPT gene have been linked to AD development but have been linked to other tauopathy frontotemporal dementia

28
Q

Mutations in which MAPT exons affect all 6 tau isoforms?

A

Exons: 9, 12, and 13

29
Q

Mutation in MAPT exon 10 affects which types of Tau isoforms?

A

Only affects Tau isoforms that have four microtubule binding repeats

30
Q

What is gliosis?

A

General term for the activation of microglia and astrocytes

31
Q

How is inflammation triggered in AD?

A

The abnormal Tau and A-beta aggregates (tangles and plaques) signal to microglia and astrocytes leading to their activation
- release pro-inflammation cytokines
- this is to try and eliminate the abnormal protein aggregates
- but this also damages the neurons and creates a feedforward mechanism that results in upregulation of A-beta and Tau in response leading to further aggregate formation

32
Q

What is one of the major vascular pathologies seen in AD?

A

Cerebral amyloid angiopathy (deposition of A-beta in walls of blood vessels in the brain)

33
Q

Other than Cerebral amyloid angiopathy, what other vascular pathologies are seen in AD?

A
  • Damage to the BBB (can contribute to issues with vascular health and blood flow to areas of the brain (dysregulated cerebral perfusion) - some areas may have hyperperfusion and hypoperfusion in others)
34
Q

What is there some evidence to show that this may be one of the earliest features of AD?

A

changes in cerebral perfusion

35
Q

What is the Amyloid cascade hypothesis in the argument over which species (A-Beta or Tau is the more toxic species and responsible for neuronal death)?

A

Aggregation of A-beta sets off a series of ds events:
- changes in A-beta production and metabolism (reduced clearance and degradation)
- leads to oligomerisation of A-beta and activation of microglial response, leading to neuronal injury
- disrupts neuronal homeostasis that induces tau hyperphosphorylation and formation of NFTs
- ultimately leading to neuronal death.

36
Q

Give three pieces of evidence in support of the Amyloid cascade hypothesis (that is the aggregation of A-beta kicks off the cascade that leads to neuronal death)

A
  • strong association between mutations in genes (APP, PS1, PS2) that increase A-beta production and the risk of developing AD
  • A-Beta has been shown to induce tau phosphorylation in vitro
  • treatment of animal models with compounds that prevent A-beta accumulation or remove aggregated A-beta show improvement in cognitive performance
37
Q

What is the Tau hypothesis in the argument over which species (A-Beta or Tau is the more toxic species and responsible for neuronal death)?

A

Tau pathology precedes A-beta plaque formation and that NFTs are the main cause of neuronal dysfunction and death

38
Q

Give four pieces of evidence in support of the Tau hypothesis?

A
  • animals (transgenic tau mice for example) that express human Tau NFTs develop cognitive impairment and neuronal death
  • treatment of animal models with compounds that prevent Tau aggregation show improvements in cognitive performance
  • Pathological studies have reported tau lesions earlier than A-beta accumulation in the human brain
  • Braak staging of tau pathology strongly correlates to the extent of cognitive and clinical symptoms observed in AD (i.e. high level of tau pathology correlates with poor cognitive performance but this isn’t observed with A-beta)
  • Dementia is also observed in other neurodegenerative diseases where NFTs are present (i.e. tauopathies)
39
Q

What is the cholinergic hypothesis in explanation of AD pathology?

A

Was the first hypothesis and forms the basis for current AD treatment (acetylcholinesterase inhibitors)
- acetylcholine neurotransmitter important for memory and attention
- cholinergic neurons are decreased in AD (lost earliest in AD)

Acetylcholine broken down by acetylcholinesterase in the synapse and the components recycled into the pre-synaptic neuron.

40
Q

How are acetylcholinesterase inhibitors used to treat AD?

A

prevent the breakdown of Acetylcholine
(loss of cholinergic neurons = less release of acetylcholine = acetylcholinesterase inhibitors keep the acetylcholine in the synapse for longer to stabilise some of the memory and attention)

41
Q

What are the current treatments for AD?

A

AChE inhibitors (Donepezil, Rivastigmine, Galantamine)

NMDA (Glutamate receptor) uncompetitive antagonist (memantine) - competes with Mg for binding in the middle of the glutamate channel so when glutamate binds the channel remains closed - no influx of calcium and excitotoxicity

(current treatment involves combining memantine with an AChE inhibitor)

42
Q

True or false: current treatments with memantine and/or AChE inhibitors can stop cognitive decline?

A

False: they can delay the progression of cognitive decline but as not treating the root cause (i.e. the NFTs or senile plaque formation) they cannot stop cognitive decline

43
Q

There is a big push to try and develop and approve what type of AD treatments?

A

Disease-modifying compounds that actually target A-beta aggregation, Tau phosphorylation and aggregation as well as removal of aggregates.

44
Q

What are some of the key drug targets for developing new AD treatments?

A

Initially driven by the Amyloid cascade hypothesis:
Prevent amyloid-beta formation, prevent aggregation, reverse aggregation or remove aggregates

But now a greater understanding for the important role Tau plays in AD so also drive to prevent or remove hyperphosphorylated tau PHFs and NFTs

45
Q

How may immunotherapy (vaccination) have been used to treat AD?

A

Active vaccinations - injection of full length A-beta42 peptide and antibodies made
- small proportion of antibodies will pass BBB and recognise aggregated A-beta42 as abnormal
- bind to plaques
- signal to microglia to phagocytose them and break them down and soluble A-beta drainage back into the plasma
- antibodies also block A-beta fibrilisation and decrease the toxicity

46
Q

What was the negative consequences of immunotherapy trials in the treatment of AD?

A

Some people developed inflammation of the meninges and died

47
Q

How may beta-secretase inhibitors have been used to treat AD?

A

Inhibit the initial step in the cleavage of APP to try and push the pathway towards the non-amyloidogenic and not generate the full length A-beta product.

48
Q

What were the negative consequences of Beta-secretase inhibitors in clinical trials?

A

Development of Beta-secretase inhibitors is hard because they need to be large since the binding site is large but also need to penetrate the BBB (which is designed to keep things out)

  • Bets-secretase is important for ion channel formation, synaptic maintenance, axon guidance, myelination and other critical neuronal functions so inhibitors also interfered with these functions and worsened cognitive decline and caused other side effects - outweighs positives
48
Q

What were the negative consequences of gamma-secretase inhibitors in clinical trials?

A
  • patients trialled with this treatment were developing cancer due to effects on Notch signalling inhibition
  • gamma-secretase is important in processing of other different type I membrane proteins (N- and E-cadherins, CD44, etc) so resulted in many other side effects
  • inhibitors also has a lack of potency, low BBB penetration and poor selectivity
48
Q

How may gamma-secretase inhibitors have been used to treat AD?

A

initially designed to inhibit NOTCH processing (which is important in development and is dysregulated in many cancers)

  • later developed ‘Notch sparing’ gamma secretase inhibitors
49
Q

List three other approaches/targets that are currently being investigated as potential treatments for AD

A
  • Metabolism - diabetes - repurpose diabetes drugs like metformin to prevent AD or reverse it to some degree
  • Inflammation - reduce gliosis
  • Vascular targets - improve blood flow - remove or reduce amyloid angiopathy
  • Neurogenesis - replace neurons that have been lost - restore neuronal function by strengthening synapses or regrowing neurons
  • Epigenetics - diet low in folate (involved in methionine - addition to DNA is epigenetic DNA modification)

BIOL354: Pathobiology (10 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions