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Pharmacology of the nervous system > neurodegenerative dementia > Flashcards

neurodegenerative dementia Flashcards

1
Q

what is dementia

A

a global impairment of higher cortical function wihch is usually progressive and irreversible

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2
Q

main symptoms of dementia

A

short term memory loss, day to day problem solving skills, perceptuomotor skills, social skills and emotional reactions

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3
Q

Common types of dementia

A

AD - progressive starting with memory
Vascular dementia - caused by impaired blood supply, sudden or step wise symptoms, variable cognition problems
FTD/PICKS - younger diagnosis. Progressive symptoms but not memory just higher cognitive function
Dementia with lewy bodies - rapid fluctuations in cognitive ability, hallucinations, motor defects occasionally

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4
Q

Protein inclusion as markers of neurodegeneration

A

AD - amyloid plaques, NFT
FTD - somtimes tangles
D with lewy bodies - lewy bodies
PICKS - pick bodies and cells

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5
Q

AD symptoms

A

deficits in memory function
disruption of normal daily living/social skills intact
LT memory failure
deficits in higher cognitive functions
spatial and temporal disorientation
dyspraxia
apathy, depression, agitation, anxiety, paranoia, delusions

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6
Q

how is brain affected pathalogically in AD

A

Apathy, narrowed gyri, increased sylvian fissure, global shrinkage, widened sulcal margins.

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7
Q

what areas of brain are affected by AD

A

Frontal lobe, parietal lobe and temporal lobe including hippocampus

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8
Q

What are markers for AD

A

Amyloid plaques and NFTs. often activated glia

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9
Q

What are NFTs composition

A

teardrop shaped tangles due to hyperphosphorylated tau filling pyramidal cells

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10
Q

What are Amyloid plaques composition

A

Contained in neuropil and made of 7-10nm thick protein fibres with amyloid Beta peptides and degenerative nerve endings

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11
Q

Causes of AD

A

94-99 idiopathic.

1-6% mendelian genetic inheritance

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12
Q

Key markers for diagnosis of AD

A

pupil dilation test with tropicamide unusually fast
altered CSF tau (high) and low AB proteins
the mini mental state exam
post mortem is definitive

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13
Q

AD therapies

A

Cholinesterase inhibitors - donepezil, galantamine, rivastigmine
Partial NMDAr antagonist - memantine

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14
Q

Cholinesterase inhibitor mechanism

A

inhibits AchE in cleft so Ach present for longer and not degraded as quickly. acts in septum pellucidum –> hippocampus, and nucleus of meynert –> widespread cortical connections

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15
Q

partial NMDAr antagonist mechanism

A

low affinity uncompetitive NMDA antagonist, binding to open conformation. limits excitotoxicity and alters aberrant synaptic plasticity

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16
Q

Hypothesis causes of AD

A

cholinergic dysfunction, glutamatergic dysfunction, amyloid, tau

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17
Q

What is normal mechanism of APP processing and how is it altered in AD

A

a secretase to release APP, y secretase to release beneficial p3.
b secretase instead of a in AD. AB then released instead of p3

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18
Q

where does a secretase cut

A

amino acid 17

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19
Q

where does b secretase cut

A

1/11

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20
Q

where does y secretase cue

A

40/42

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21
Q

what is the gene for a secretase

A

ADAM 10/17

22
Q

What is the gene for b secretase

A

BACE - 1

23
Q

What are the proteins that make up y secretase

A

presenelin 1/2, nicastrin, aph1 and pen2

24
Q

What do APP mutations cause

A

increase b secretase cleavage - EOAD

25
Q

what do PSEN1/2 mutations cause

A

increase y secretase activity - EOAD

26
Q

what is the old hypothesis for AD and who came up with it

A

Hardy and HIggins, 1992. Amyloid cascade hypothesis –> amyloid leads to NFT and cell death

27
Q

Genetic evidence for amyloid hypothesis

A

Familial Mendelian AD is linked to mutations in APP, PSEN1 and 2
ApoE isoform 4 is predisposing to EOAD

28
Q

What is ApoE4 and what does it do

A

lipid transporting protein that can assist in clearance of AB. isoform 4 not as effective

29
Q

How is familial mendelian AD linked to mutations in APP, PSEN1 and 2

A

EOAD. increase in AB1-42 and AB1-40

includes trisomy of chromosome 21 where APP gene is located

30
Q

what is most toxic form of AB

A

AB-1

31
Q

what does APP do

A

alters neuronal excitability

protective functino recently found

32
Q

what is APPswe

A

EOAD mutation

33
Q

what does APPswe do

A

not active - no calcium measure shown. increases l type ca currents. APPswe mouse has defects in neuronal structure. Spine number decreased close to plaques

34
Q

what is tau

A

microtubule associated protein which stabilises

35
Q

What does tau do in disease

A

hyperphosphorylate
dissociate from microtubules
misfolding and aggregation into NFTs

36
Q

how is tau hyperphosphorylated

A

upregulation if kinases or down regulation of phosphatases

37
Q

Tauopathy pathology

A

no plaques but cell death

38
Q

in rTg4510 model of tauopathy, what is mutated?

A

P301L mutation in MAPT gene found in FTDP-17

39
Q

does AB in brains always cause cognitive impairments?

A

no

40
Q

soluble or plaques as better indicator?

A

soluble as better correlation to decline in cognition

41
Q

what does soluble AB on cultured neurons cause

A

EPSC reduction

42
Q

what is first thing that AB affects?

A

synaptic transmission

43
Q

what does APP mutation not do?

A

produce amyloid

44
Q

Mutated APP with GFP experiment results and problems

A

APP mutation doesnt produce amyloid.
overexpression so may not be related to disease
AB is usually extracellular whereas intra in experimenty

45
Q

do AB transgenic mice studies influence tau formation?

A

yes

46
Q

what is the relationship between microglia and AB?

A

microglia found near plaques and directly activated by AB

47
Q

what is TREM2

A

genetic factor for AD which may lead to activated microglia

48
Q

what is the structure of AB fibirls

A

s shaped stack formed by AB1-42 but not AB1-40. conformation of monomers different

49
Q

main issues of b secretase inhibitors?

A

pharmacokinetics

50
Q

y secretase inhibitor problems

A

accelerated cognitive decline as no p3. also targets notch

51
Q

potential mechanism of y secretase modulators

A

preferential AB38>42 without notch 1 cleavage

52
Q

what is solanezumab

A

monoclonal antibody directed to mid section of AB. failed phase 3

Pharmacology of the nervous system (9 decks)

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