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E: Neuropsychopharmacology > Alzheimer’s disease and its treatment > Flashcards

Alzheimer’s disease and its treatment Flashcards

1
Q

Dementia?

A

A syndrome

Usually of a chronic or progressive nature.

Deterioration in cognitive function- ie the ability for process thought.

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2
Q

What does dementia effect?

A

Affects memory

Thinking

Orientation

Comprehension

Learning capacity

Lanaguage etc

Consciousness is not effected

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3
Q

What percentage is dementia surferrers caused by alzheimers?

A

60-70%

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4
Q

Mixed dementia?

A

Mixture of different types of dementia

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5
Q

What are the numbers of dementia sufferers expected to do every 25 years

A

Numbers expected to double

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6
Q

AD brain?

A

Brain has shrunk

Extracellular plaques and intracellular neurofibrillary tangles

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7
Q

Name the 6 important stages of the history of AD research?

A
  1. Chloinergic hypothesis
  2. Discovery of amyloid and tau.
  3. Oxidative damage.
  4. Genetic mutations
  5. Importance of inflammation
  6. Immunotherapy (antibodies against amyloid)
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8
Q

What happens to an Alzheimers brain?

A

Severe cell loss.

Spreads from hippocampus right through into the cerebellum and into the spinal cord.

Damge to proteins and protein accumulations

Damage to lipids and inflammation

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9
Q

Late onset alzheimers?

A

>95% of dementia cases.

>65 yo.

Genetic link with APOE

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10
Q

Early onset Alzheimers disease?

A

5% of AD cases

Present in >65 yo.

Genetic link with APP, PSEN1, PSEN2

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11
Q

Apolipoprotein E (ApoE)

A

Major component of very low-density lipoproteins.

Remove excess cholesterol from the blood and carry it to the liver.

Most abundantly produced apoprotein

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12
Q

ApoE role?

A

Cholesterol and lipid delivery to neurones

Cholesterol transport to the blood to the liver for processing.

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13
Q

What secretes ApoE?

A

Secreted by glial cells in nascent high-density lipoproteins-like particles.

They contain phospholipids and cholesterol

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14
Q

What is the ApoE concentration in cerebrospinal fluid?

A

5 µg/ml

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15
Q

ApoE receptors?

A

LDLR (low desity lipoprotein receptor)

LRP1 (LDLR-related protein)

Undergo endocytosis to transport ligands from the cell surface to intracellular compartments.

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16
Q

ApoE is?

How many forms of it?

A

glycoprotein

3 common forms (each differ from each other by 1/2 AAs)

ApoE2

ApoE3

ApoE4

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17
Q

ApoE4

A

Risk of AD is high with one allelle and must greater with two alleles.

60% are ApoE carriers.

Reduces the age of this onset disease.

More extensive plaques and tangles.

Higher CSF concentration of soluble Abeta.

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18
Q

ApoE effects on amyloid?

A

ApoE contains paritcles sequester Aβ that modulates the cellular uptake of the complex by receptor-mediated endocyotsis.

Modulate Aβ removal from the brain by systemic circulation (transport across the blood-brain barrier)

ApoE facilitates the binding and internalisation of Aβ or its clearance

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19
Q

Targeting ApoE?

Name the 5 Therapeutic approaches

A
  1. Conversion of ApoE4 to ApoE3.
  2. Increase the lipidation.
  3. Interference interaction between ApoE4 and amyloid beta (Aβ).
  4. Reversal of the effects of ApoE4.
  5. Gene transfer
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20
Q

What does ApoE3 and ApoE4 do?

A

AS1

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21
Q

TREM2?

A

Triggering receptor expressed on myeloid cells 2.

increaase chance of AD by 3 fold

Rare

Found in microglia.

Related to parkinson’s

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22
Q

PLD3?

A

little known on function.

Overexpression leads to reduction in Aβ levels

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23
Q

Name the 3 dominatly inherited mutations involved in amyloid processing?

A
  1. β-amyloid precusor protein
  2. PSEN1
  3. PSEN2
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24
Q

β-amyloid precursor protein (APP)?

A

Alternatively spliced to produce 3 transcripts

APP695, APP751, APP770

Proteolytic processing of APP leads to production of rfragments and the amyloidogenic pathways.

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25
Q

PSEN1/2?

A

PSEN1: Located at chromosome 14

PSEN2: located at chromosome 1

PSEN1/2 are important for the γ-secretase complex.

This cleaves APP into Aβ fragments

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26
Q

3 main pathways causing AD?

A
  1. The immune system and inflammatory response
  2. Cholesterol and lipid metabolism
  3. Endosomal vesicle recycling
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27
Q

What are the 5 major hypotheses that causes AD?

A
  1. Cholinergic and glutamatergic
  2. Amyloid and Tau
  3. Oxidative stress
  4. Inflammation
  5. New targets
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28
Q

Cholinergic hypothesis?

A

Selective loss of cholinergic projections from hippocampus and frontal campus.

Muscarinic receptor antagonist coud mimic the deficits.

Reversed using AChE inhibitors

29
Q

Name the 4 current therapeutics?

A
  1. Tacrine
  2. Donepezil
  3. Galantamine
  4. Rivastigmine
30
Q

Tacarine?

A

Short half life

Need to take 4 times a day (not great with memory problems)

31
Q

Donepezil?

A

70Hr half life

32
Q

Galantamine?

A

Once a day

Interacts with AChRs

33
Q

Rivastigmine?

A

transdermal patch

2x daily

34
Q

Acetylcholinesterase inhibitors? (AChE inhibitors)

A

Show consistent, small treatment effects in mild AD

Effects are only temporary.

Effects seen within 4 months

35
Q

Glutamate/Calcium Dysregulation hypothesis?

A

Aβ oligomers enhance the presynaptic release of glutamate.

Blocks glutamate uptake by astrocytes though glutamate transporters. Leads to Tau phosphorylation and neuronal death.

36
Q

Memantine?

A

A voltage-dependent, non-competitive NMDA receptor antagonist.

Used to manage AD- for peopel that cannot take AChE inhibitors

37
Q

Amyloid hypthoesis?

3 therpeutic strategies?

A
  1. Prevent Aβ production
  2. Prevent aggregation
  3. Promote removal
38
Q

Prevent Aβ production?

A

beta-secretase inhibitor

gamm-secretase inhibitor

39
Q

Prevent aggregation?

A

A β oligomerisation inhibitors.

Tau aggregation inhibitors

40
Q

Promote removal?

A

Vaccines

41
Q

Name the 3 drug trails targeting amyloid processing?

A
  1. alpha-secretase inducer
  2. gamm-secretase inhibitor
  3. BACE inhibitors:
42
Q

Tau?

A

Highly soluble microtubule-binding protein.

Mutations in tau cause frontotemporal dementia.

Hyperphosporylation of tau destablises micrtubules, causing neuronal dysfunction.

43
Q

Oxidative stress?

A

Oxygen helps us burn sugar to produce energy.

Need antioxidant defences so it does not damage cell strucutres.

Oxidative stress occurs when free radical production outstrips the ability of the cell to neutralise it

44
Q

Name the 3 defences against oxidants?

A
  1. Glutathione system
  2. Superoxide dismutase
  3. Catalase
45
Q

Name the other 7 causes of oxidative stress?

A
  1. Ageing
  2. Environmental pollution
  3. Food contaminants
  4. Cigarettes
  5. Amyloid
  6. Inflammation
  7. Injury
46
Q

Oxidative stress in AD?

A

Implicated in the pathology of AD.

Free radical damage to DNA is evident early in AD.

47
Q

Amyloid and tau patholgies

A

Alzheimer’s disease (AD) is characterized by extracellular deposition of β-amyloid (Aβ)

intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles

48
Q

Name the 2 antioxidants that are used as treatment for dementia?

A
  1. Vitamin C- does not get into the brain- metabolites of vitamin C (DHA) can get into the brain and protect it from a stroke. DHA is broken down rapidly.
  2. Vitamin E: does get into the brain however the conc is tighly controlled and even high dosage will not increase the brain concentration.
49
Q

Inflammation?

A

Use of anti-inflammatory agents.

People with arthritis less likely to get AD.

NSAIDS did nothing

Statin?

50
Q

What encodes for nAChRs?

A

8 alpha (alpha 2->9)

3 beta ( beta2->4)

51
Q

Heteromeric nAChRs receptor is formed be?

A

alpha 2-6

beta 2-4 subunits

52
Q

Homomeric nAChRs is formed by?

A

alpha 7-9 subunits

53
Q

80% of nAChRs in the CNS are?

A

alpha 4 beta 2

54
Q

10% of the nAChRs in the CNS are?

A

alpha 7

55
Q

Early AD:

Aβ and alpa7 nACh recepotr

A

the expression overlaps.

Aβ induces expressio of the alpha7 nACh receptor

56
Q

alpha7 nACh receptor activation

A

Facilitates neurotransmission and synaptic plasticity.

Induces LTP.

Supports learning and memory.

57
Q

alpha7 interaction with Aβ

A

found in amyloid plaques.

Can mediate internalisation of aβ

Mediates inflammatory response to Aβ

Blocks amyloid toxicity.

58
Q

Agonist of the alpha7 nicotinic repector?

Positive and negative effects?

A

For: conitive enhancing, anti-inflmmatoyr, induces amyloid phagocytosis.

Against: rapid desensitisation

59
Q

Antagonist for the alpga7 nicotinic receptor:

Positive and negative effects?

A

For: block adverse effects of Aβ- intracellular accumulation and toxicity.

Against: not cognitive enhacing, block synpatic plasticity.

60
Q

Modelling MCI

A

Impairments in olfactory discrimination and odur recognition memory.

Patients with MCI combined with olfactory deficienceies are highly to progress to AD.

61
Q

OST?

A

Odour span task.

Based on the digit span task.

Model requires the idenfitication of a novel oduour from an expanding list of previously experienced odours.

62
Q

Humanin?

A

The peptide is made by the mitocondria and exported to neighbouring cells to protect amyloid toxicity and ischemic.

Used as a biomarker for early AD.

Reverses defecits of damage and oxidative stress.

Not expressed noramlly- only when there is damage on surviving neurones.

63
Q

IGFBP3?

A

Involved in amyloid clearance

Also enduces heart problems and cancer

64
Q

HNG drug target?

A

HNG: analog of human increases span length at microscopic doses.

Improves olfactory working memory

65
Q

Current AD treatments?

A

Provide limited (9-12mnths) respite in a subpopulation of patients

Afford limited symptomatic relief

66
Q

Diseas-modifying treatments?

A

Pathological hallmarks appear to be tombstome marks rather than signpost to the underlying disease.

67
Q

A model for MCI?

A

Deficits in olfactory working emory precede amyloid deposition in TG2576

68
Q

OST examples?

A

Demonstarte cognitive enhancing.

Nicotine and a7 nACh receptor agonist

Humanin

E: Neuropsychopharmacology (9 decks)

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