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Molecular Neuroscience II > 10 - Alzheimer's Disease I > Flashcards

10 - Alzheimer's Disease I Flashcards

Useful Links: http://en.wikipedia.org/wiki/Apolipoprotein_E#Alzheimer_disease

1
Q

What are two reasons for the increase in Alzheimer’s?

A
  • Longer lifespan

- Better diagnostic techniques

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2
Q

What is apolipoprotein E (ApoE)?

A

Involved in the transport of lipids. Mainly produced by astrocytes and shuttles cholesterol into neurons.

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3
Q

True or false? Alzheimer’s doesn’t affect motor control

A

True

This is in contrast to other neurodegenerative diseases (eg. HD and MS)

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4
Q

Why might smoking prevent Alzheimer’s?

A

Because it stimulates cholinergic neurons. Stimulating cholinergic neurons is one treatment for AD

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5
Q

What is Tau necessary for?

A

Necessary for transport, part of cytoskeleton. Connected to microtubules.

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6
Q

True or false? Expressing hyperphosphorylation of Tau will mimic Alzheimer’s disease in animals.

A

False, this does not result in a model for AD

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7
Q

How can PET scans diagnose Alzheimer’s disease?

A

Measures glucose, which decreases with Alzheimers (but also diabetes).

Shows accumulation of beta amyloid.

A new tracer for Aβ called Florbetapir was released, which allows greater resolution.

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8
Q

True or false? Alzheimer’s related to amyloid precursor protein gene and this is heritable.

A

True

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9
Q

What two enzymes are needed to synthesize beta amyloid from amyloid precursor protein?

A
  • β-secretase

- γ-secretase

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10
Q

Broadly, what does RAGE do?

A

Transports beta amyloid across the blood brain barrier into the brain

Targeting this mechanism may be a treatment

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11
Q

What are the inflammatory process with beta amyloid?

A
  • Astrocytes and microglia produce pro-inflammatory and neurotoxic effects
  • Can result in degradation of beta amyloid protein
  • In time, production of pro inflammatory factors begin harming the brain
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12
Q

True or false? There is no single perfect mice model of Alzheimer’s disease

A

True

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13
Q

How are Alzheimer’s disease model mice made?

A
  • Using a human transgene for amyloid protein overexpressed in the mice
  • Tetracycline can inhibit expression of amyloid transgene
  • Apolipoprotein models can be made, but no changes similar to Alzheimer’s patients (besides cholesterol homeostasis)
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14
Q

What is the most respected model of Alzheimer’s Disease in mice

A
  • triple transgene model:
  • Overexpression of Beta amyloid
  • Overexpression of tau
  • Overexpression of apolipoprotein
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15
Q

What do therapeutic approaches to Alzheimer’s disease focus on?

A

Reducing amount of beta amyloids

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16
Q

What does stimulation of α-secretase result in?

A

Decrease in amount of beta amyloids

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17
Q

How can the buildup of hyperphosphorylated tau polymers be prevented? (4)

A
  • Methylene blue can prevent buildup of aggregates
  • Inhibiting of tau kinases, can trigger other important physiological protein-protein interactions (unwanted side effects)
  • Microtubule stabilizers
  • HSP90 inhibitors prevent buildup of Tau
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18
Q

In mouse expressing buildup of beta amyloid, antibodies against the plaque didn’t affect the buildup. What combo is affective?

A

Antibodies plus doxycycline (inhibits APP synthesis) is effective for removal of plaque deposits

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19
Q

What types of diets can prevent Alzheimer’s?

A

Mediterranean like diets

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20
Q

What is the most common form of dementia?

A

Alzheimer’s

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21
Q

What are five important things that a post mortem neuropathology of Alzheimer’s disease brain reveals?

A
  • Senile plaque made of β-amyloid (Ab)
  • Neurofilaments made of hyperphosphorylated tau protein
  • Cortical and subcortical degeneration (atrophy of neuronal tissue and increase of volume of cerebral ventricles)
  • Amyloid angiopathy resulting from deposition of insoluble aggregates of β-amyloid peptide in the walls of blood vessels
  • Cortical Lewy bodies (aggregates of α-synuclein and ubiquitin in neurons) or TDP-43-positive inclusions
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22
Q

What similarity do Alzheimer’s brains and Parkinson’s brains have (besides neurodegeneration)?

A

Cortical Lewy bodies (aggregates of α-synuclein and ubiquitin in neurons)

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23
Q

What similarity do Alzheimer’s brains and ALS brains have (besides neurodegeneration)?

A

TDP-43-positive inclusions (TAR DNA-binding protein 43)

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24
Q

What is the proposed National Alzheimer’s Project Act (NAPA)?

A

Main goal is to prevent and effectively treat Alzheimer’s by 2025

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25
Q

True or false? The prevalence of Alzheimer’s disease is rising

A

True

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26
Q

How many people suffer from AD?

A

5 million americans

26 million worldwide

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27
Q

What demographic is most likely to be diagnosed with AD?

A

Females (2/3 more) over 65 yo

Possible role of estrogen/men die earlier

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28
Q

How many years does AD neurodegeneration start before clinical onset?

A

20-30 years

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29
Q

Late onset AD (over 65) is associated with what allele of what gene?

A

ε4 allele of Apolipoprotein E gene

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30
Q

What type of inheritance is associated with amyloid precursor protein (APP), presenilin-1 (PSEN1) and presenilin-2 (PSEN2) genes?

A

Autosomal dominant inheritance

1-5% of onsets are from early onset in familial Alzheimer’s disease

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31
Q

How is Down Syndrome associated with AD?

A

Trisomy 21 (Down’s) show early onset of dementia

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32
Q

What is the physiological function of Amyloid precursor protein (APP)?

A

18 Alzheimer’s related mutations are known, but the physiological function is unknown.

  • Believed it is involved in synaptic formation, repair, signalling and cell adhesion.
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33
Q

What are the two main types of symptoms in AD?

A
  • Memory-speech-vision-attention (can remember by Mount Saint Vincent A)
  • Behavioural changes
34
Q

List four memory-speech-vision-attention symptoms for AD

A
  • Amnesic mild cognitive impairment in early stages
  • Deficit in short term memory (degradation in hippocampus and entorhinal cortex)
  • Difficulty with verbal communications and visual skills, but can learn motor skills
  • Constructional apraxia (inability to combine given elements into a meaningful whole) in late stages
35
Q

List 4 behaviour changes associated with AD

A
  • Depression
  • Agitation, anxiety and irritability (sometimes becoming aggressive)
  • Sometimes apathy
  • Social isolation and withdrawal
36
Q

What are 5 proposed causes of AD?

A
  • Cholinergic deficit
  • Ab build up
  • Tau protein aggregation
  • Myelin degeneration
  • Inflammation
37
Q

What is the main role of Tau protein?

A

Soluble microtubule-binding protein

Stabilization of microtubules in axons as tracks for axonal transport and cytoskeletal elements for neuronal development.

38
Q

Are Tau mutations a cause of AD?

A

no

39
Q

What are two gross neuroanatomical changes from Alzheimer’s disease that can be seen with MRI?

A
  • Atrophy of the forebrain

- Enlargement of the lateral ventricles

40
Q

Why is early diagnosis of AD problematic? What is the best way to diagnose it? List for criteria that ‘can’ be used for this approach.

A

It has a long prodromal period (Pre-clinical period)

Multiple biomarkers is the best approach, including:

  • antibodies in blood,
  • serum protein change,
  • decrease in desmosterol (metabolized to cholesterol)
  • Decrease in CSF ab1-42 levels
41
Q

What is C-PIB?

A

A PET radiotracer that binds to fibrillary beta-amyloid

Accumulation in cortical areas is an early indicator of AD

42
Q

What is the clusterin-encoding CLU gene?

A

Located on the short arm of chromosome 8. Functionally related to apolipoprotein e (APOE), it is sometimes called apolipoprotein J and is associated with AD

43
Q

Describe the synthesis of beta amyloid plaque formation for familial AD

A
  • Mutation in APP or trisomy 21 leads to synthesis of amyloid precursor protein (APP)
  • β-secretase cleaves APP into soluble amyloid precursor protein β (sAPPβ)
  • sAPPβ is cleaved by γ-secretase (induced by presenilins 1 and 2 (PS1,PS2) and/or mutations) into beta-amyloid
  • beta-amyloid forms into oligomers and plaques/LTP impairment follow and eventually causes synaptic loss and neuronal death
  • apolipoprotein E (APOE), clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM) and CR1 (erythrocyte complement receptor 1) promote aggregation into plaques
44
Q

What is RAGE? How is it associated with AD?

A

Receptor for advanced glycation endproducts, a transmembrane protein that belongs to the immunoglobulin superfamily

Expression of RAGE elevated in AD patients and mice AD models

45
Q

What does RAGE do in AD?

A

Binds with Ab, which triggers signalling cascades resulting in neuronal toxicity and synaptic dysfunction

46
Q

What does membrane bound RAGE do in AD?

A

Membrane bound RAGE mediates Ab transport across blood brain barrier, resulting in Ab-induced NF-kB activation and monocyte/macrophage migration across the BBB and in consequence stimulating and amplifying of inflammatory responses

47
Q

What does soluble RAGE do in AD? How are sRAGEs produced (name the two enzymes)

A

Soluble RAGE (sRAGE) exhibit opposite effect of membrane bound RAGE (which shuttles Ab into brain)

serving as a decoy receptor for Aβ, which inhibit neuronal RAGE-Ab signalling and RAGE- mediated BBB crossing of Ab.

A sRAGE is produced by proteolytic cleavage of the membrane bound form by the metalloprotease 10 (ADAM10) and matrix metalloproteases (MMPS).

48
Q

What does trophic deprivation (removal of growth factor and adding antibodies: anti-NGF, anti-BDNF and anti-NT3) in neuronal cultures do?

A

Stimulates cleavage of amyloid precursor protein (APP) by BACE1, releasing soluble APPβ (sAPPβ)

  • Fragments of N-APP are a ligand for Death REceptor 6 (DR6), the N-APP/DR6 interaction triggers apoptosis via caspase-3 dependent mechanism in the neuronal cell body and via caspase-6 in the axon.
49
Q

How do glial cells attempt to prevent Ab formation?

A
  • Ab and neurofibrillary tangles (NFT) induce inflammatory response from astrocytes and microglia
50
Q

Ab and neurofibrillary tangles asociated with AD trigger astrocytes and microglia to produce what pro-inflammatory and neurotoxic factors? (8)

A
  • transforming growth factor beta (TGF-beta)
  • Tumour necrosis factor alpha
  • Interleukin-1
  • CC-Chemokine ligand (CCL)
  • Anti-chymotrypsin (ACT)
  • Reactive oxygen species (ROS)
  • Cyclooxygenase 2 (COX2)
  • Microglia express scavenger receptors (SRs) that mediate phagocytosis of Ab, such as CD36 and SR-
51
Q

How can microglia cells degrade Ab? Why is mutations in complement receptor 1 (CR1) gene a risk factor for Alzheimer’s disease?

A

Releasing Ab degrading enzymes, such as:

  • Insulin-degrading enzyme (IDE)
  • Complement component 1q (C1q), which co-localizes with amyloid deposits and triggers a complement cascade, including the formation of the membrane attack complex (MAC)
  • Mutations in complement receptor 1 (CR1) gene, which is important for enabling the humoral immune response, are risk factors for AD
52
Q

What are the 4 types of Alzheimer’s mouse models?

A
  • APP transgenic models
  • Apolipoprotein E ε4 transgenic models
  • Presenilin 1 models
  • Presenilin 2 models
53
Q

List the two APP transgenic models for Alzheimer’s disease

A
  • PDAPP transgenic mice (express V717F mutant APP from the human ‘platelet derived’ growth factor β polypeptide (PDGFb) promoter. (other important models include: Tg2576, App23 and Tg-SwDl mice)
  • TetO-APPSwe/Ind mice express human APP under control of tetracycline responsive promoter. 10-30x increase of APP. Doxycycline administration inhibited APP expression up to 95% and reduced Ab production, clearance of accumulated Ab was very slow
54
Q

What is the apolipoprotein E ε4 transgenic model of AD?

A

ApoE4 knockin mice (contain human ApoE4 in place of mouse ApoE4) show brain increase in cholesterol levels, but neither elevated Ab nor neuronal degeneration

55
Q

Describe the presenilin 1 mice model of AD. Discuss the efficacy of this in modelling AD.

A

Presenilin 1 is knocked out

  • Homozygous mice die in perinatal development, embryos show severely impaired neurgenesis
  • Heterozygous PS1-KO mice are viable and fertile. Conditional homozygous deletion of PS1 in floxed mice through crossing with Cre mice resulted in viable and fertile mice with decreased levels of Ab40 and Ab42 peptides, but an accumulation of other APP fragments. Overall PS1 mutations alone did not induce AD-like effects
56
Q

What is presenilin 1 (PS1)?

A

A component of the intermembrane γ-secretase complex that processes APP to produce an APP intracellular domain

57
Q

What do PS1 and APP mutations combined together and expressed in mice show? (3)

A
  • Enhanced Ab deposition
  • Ab related pathology
  • Cognitive deficits
58
Q

Describe Presenilin 2 mice models of AD. Is this a good model for AD? Why?

A
  • PS2 mutations are a much less common cause of AD than mutations in APP and PS1
  • PS2 null mice exhibit lung abnormalities, but no AD symptoms
59
Q

What is the triple-transgenic model of AD mice?

A

3xTg-Ad

  • Displaying beta amyloid placques
  • Tau laden neurofibrillary tangles
  • age-dependent alterations in memory function
60
Q

Is there a single mouse that exhibits all the symptoms observed in human Alzheimer’s disease?

A

no

61
Q

What are the standard treatments for improving cognitive impairment in AD patients for mild to moderate OR moderate to severe AD? What is another type of treatment that is common for all cases of AD?

A

Mild to moderate AD
- Acetylcholinesterase inhibitors (cognitive function)

Moderate to severe AD
- NMDA antagonist (cognitive function)

Additional treatment may target common non-cognitive neuropsychiatric symptoms, such as depression and psychosis.

62
Q

How is the majority of APP processed in a healthy person? How can this be taken advantage of with AD treatment?

A
  • α-secretase cleaves APP within the beta amyloid region and subsequent cleavage by γ-secretase yields a soluble N-terminal fragment (P3) and a membrane bound C terminal fragment (AlCD)
  • Stimulating α-secretase pathway will reduce Ab amounts and produce soluble N-terminal fragments (sAPPa), which will exhibit neuroprotective function.
63
Q

What is an alternative treatment to stimulating the α-secretase pathway?

A
  • Inhibiting the γ-secretase and β-secretase pathways
64
Q

What does stimulation of Neprilysin do?

A

Promote the degradation of beta amyloids

65
Q

What does inhibition of the receptor for advanced glycation end products (RAGE) do?

A

Prevent Ab from traversing the blood brain barrier

66
Q

True or false, vaccines may be used to prevent amyloid beta plaque formation?

A

True, by directing vaccines at Ab/oligomers/plaques the clearance of Ab is promoted.

67
Q

What is Rosiglitazone and how can it treat AD?

A

Anti-diabetic drugs

Anti-inflammatory properties may allow it to treat AD

68
Q

Which isoform of beta amyloid has the highest tendency to form aggregates?

A

Aβ32

Next, amyloid plaque.

69
Q

How do glia contribute to effect the amyloid cascade?

A

Apolipoprotein E (APOE) synthesized by glia directly affect the amyloid cascade via effects on Ab deposition and/or clearance.

70
Q

Why is it difficult to develop therapeutic approaches aimed at Tau? (2)

A
  • Neurofibrillary tangles can be inhibited by kinases, but there is a high risk of unwanted effects and the BBB prevents passage into brain.
  • Methylene blue can dissolve Tau filaments, but could effect other vital protein-protein interactions in the brain (hard to make selective)
71
Q

What is the best approach to AD therapy? (eg. what should be targeted)?

A

Tau and beta amyloids should be combinationally targeted, rather than only one or the other.

72
Q

List some Tau therapeutic approaches (10)

A
  • Phosphatase (PP2A) activators
  • Active and passive immunization
  • Tau kinase inhibitors
  • Microtubule stabilizers
  • HSP90 inhibitors
  • Tau assembly inhibitors
  • Antioxidant/mitochondrial strategies
  • Autophagy enhancers
  • Dendritic tau (Fyn) blockers
  • Tau reduction
73
Q

How does amyloid specific antibody work? (4)

A
  1. Amyloid specific antibodies trigger a phagocytic response by microglia (microglia mediated)
  2. Antibodies reach amyloid deposits in the brain and resolve them directly through interaction of the antibody with the amyloid deposit (direct resolution)
  3. Antibodies act as a peripheral sink for soluble Ab species (peripheral sink - like vacuum)
  4. Antibodies bind to oligomeric Ab species, blocking their toxic effects without immediate impact on amyloid load (blockade of toxic oligomers)
74
Q

List what each of these antibodies do in AD treatment:

Semagacestat
Bapineuzumab
Solanezumab
Intravenous immunoglobulin G

A

Semagacestat - γ-secretase inhibitor (reduces Ab synthesis)

Bapineuzumab - humanized monoclonal antibody to Ab (microglia mediated clearance)

Solanezumab - Humanized monoclonal antibody to Ab (Peripheral sink mechanism)

Intravenous immunoglobulin G - Contains endogenous polyclonal antibodies to Ab (peripheral sink mechanism)

75
Q

What are some induced unwanted effects from amyloid-specific antibodies? (3)

A
  • Bapineuzumab can induce vascular abnormalities (eg. microhaemorrhages and oedema)
  • Reason is that buildup of Ab around capillaries can change the local structure of vascular system
  • Rapid removal by antibodies makes vessel walls more prone to break or swelling
76
Q

How might the pathological process of AD be reversed? (2)

A

Tet-off APP transgenic mice treated with doxycycline (inhibited APP synthesis) and peripherally injected with anti-Ab monoclonal antibodies show significant reduction in Ab buildup after 6 months in treatment

  • Antibody treatment
  • APP suppression
77
Q

NSAIDS (COX-1 and COX-2 inhibitors) cause what sort of affect in AD therapy?

A

Can prevent developing AD, but not treat clinical AD.

78
Q

What affect do HMG-CoA reductase inhibitors (statins) with acyl-CoA cholesterol acyltransferase inhibitors show in AD model animals?

A

Lowered Ab levels

79
Q

Insulin resistance may (accelerate or or decelerate) Alzheimer’s pathogenesis?

A

Accelerate

Insulin-sensitizing peroxisome proliferator-activated receptor y (PPARy) agonists can beneficial for treating AD because of this.

80
Q

Where are there no APOE directed treaments

A

Complex function of the protein

Molecular Neuroscience II (7 decks)

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