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Molecular Pharmacology > Lectures 7-18 > Flashcards

Lectures 7-18 Flashcards

1
Q

What are the three main ways of attacking the amyloid pathway?

A

(i) Reducing AB formation (e.g. BACE inhibition or Y-secretase modulation) (ii) Increasing AB clearance (degrading enzymes/modulation of gene transcription/antibodies) (iii) Other mechanisms such as preventing aggregation

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2
Q

Who was Auguste Deter?

A

Patient in which Alois Alzheimer classified Alzheimer’s disease; had a PS1 mutation which probably caused the disease

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3
Q

What are the three hallmark features in the brain of AD?

A

Senile plaques, neurofibrillary tangles and amyloid core

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4
Q

What are the three types of AD?

A

Definite AD- clinical diagnosis with histological confirmation
Probable AD- typical clinical features without histology
Possible AD- atypical clinical features, no other cause, no histology

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5
Q

What are the typical clinical features of AD?

A

Short term memory loss; language problems; disorientation; mood swings; behavioural issues; loss of motivation; motor/sensory problems; loss of bodily functions
Death occurs between 3-20 yrs after onset

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6
Q

What tests of cognitive function are available for AD?

A

AD Assessment cognition subscale (ADAS-Cog)
Blessed dementia rating scale
Cambridge neuropsychological test automated battery (CANTAB)
Mini-mental state exam (MMSE)
Neuropsychiatric inventory

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7
Q

What are the two functions of voltage-gated ion channels?

A

i) let ions across a membrane rapidly with selectivity ii) open and close pore in response to changes in membrane potential

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8
Q

Which is the most selective ion channel?

A

Potassium

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9
Q

How is ion selectivity achieved?

A

i) ions initially in a hydration shell (surrounded by water)
ii) channel interacts more strongly with ion than water does by presenting polar groups for interaction
iii) ion can only fit through selectivity filter in dehydrated state
iv) multiple occupancy high affinity binding- energy favourable binding combined with electrostatic repulsion with other ions pushes ions through quickly

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10
Q

What are the two states of voltage dependent gating?

A

i) Voltage sensing domain senses membrane changes

ii) movement of voltage sensor is coupled with opening and closing of channel pore

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11
Q

what are the two types of drugs that target voltage gated ion channels?

A

i) Ion channel pore blockers

ii) Gating modifiers (e.g. ball and chain mechanism/collapse of selectivity filter)

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12
Q

Describe the topology of a VG ion channel

A
  • Have four subunit domains
  • Each domain has six membrane spanning domains
  • Voltage sensor is found at S4
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13
Q

How is the structure of potassium VG channel different to that of the calcium and sodium VG channels?

A

Potassium has four separate polypeptides comprising the domains, whereas with sodium and calcium are composed of a single polypeptide

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14
Q

What is the function of the auxiliary subunits (beta subunits)?

A

Arrange themselves around the central pore and ensure: the pore is traffics properly, and they also regulate the function of the pore

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15
Q

Which channel family is the most diverse?

A

Potassium; four subunits make a tetramer channel complex which can be composed of many different subunits; 12 differnet subfamilies with a variety of genes within each family

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16
Q

What mechanisms contribute to the diversity of the potassium channel family?

A
  1. Large number of genes encode Kv channels and some encode modifier subunits (Kv 5,6,8,9 dont form functional channels alone)
  2. Alternative splicing of RNA transcript
  3. Heteromultimerization for Kv1, Kv7 and Kv10
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17
Q

How was the first potassium channel structure solved and why did it take so long?

A

First K channel structure was solved in bacteria. To get a crystal structure, large quantities of protein are needed; mammalian Kv cannot be produced in high amounts in bacteria as it aggregates; realised the function of bacterial K channels was same as mammals

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18
Q

What are the functions of the subunits in the potassium channel?

A

S1-S4 is the voltage gating part of the protein
S5-S6 form the potassium selective channel
Signature sequence GYGVT, within the P loop forms the selectivity filter

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19
Q

In bacteria, what does the selectivity filter look like?

A

M2 (S6) lines the pore and P-loop forms selectivity filter; has enough space that 4 ions can bind; carbonyl backbone groups are arranged to simulate water binding to the ion; only 2 ions ever bind at one time

20
Q

What is the activation pore and how is it structured?

A

Towards the intracellular side and involves a glycine hinge; S4 segment is the voltage sensor; when membrane depolarises, it moves outwards; S4-S5 linker forms a helix parallel to membrane; presses against S6 and couples movement of S4 upwards or downwards to movement of itself up or down

21
Q

What are the two projection systems in the brain that use acetylcholine as a neurotransmitter?

A
  1. Brainstem (penduculopontine nucleus)

2. Basal forebrain (projects to the cortex and hippocampus)

22
Q

How are the two acetylcholine systems implicated in AD and form the cholinergic hypothesis?

A

Deficits in cholinergic system associated with impaired cognition, and a loss of cholinergic neurons are seen in AD; 3 British groups reported:

  • Loss of choline acetyltransferase
  • Loss of ACh degrading enzyme ACh esterase
  • Sparing of postsynaptic muscarinic receptors
23
Q

What three inhibitors of ACh are used to treat AD?

A

Donepezil, galantamine, rivastigmine

24
Q

How was the amyloid hypothesis of AD developed?

A

Found that sequence of amyloid protein in AD patients was identical to amyloid found in Down’s syndrome patients. As AD pathology occurs in all Downs patients, link was suggested. Amyloid precursor protein isolated as a result

25
Q

What is the structure of the amyloid precursor protein?

A

Is 695 amino acids long and has parts within and outside the membrane- located on chromosome 21

26
Q

What are the two forms of the amyloid protein and which one is toxic?

A

AB40 is non toxic (more abundant) and AB42 is toxic (less abundant).

27
Q

What is the amyloid cascade hypothesis?

A
  • Processing of APP can occur in two pathways:
    i) cleavage within ABP by y-secretase generating AB40
    ii) cleavage in the endosomal lysosomal compartment, resulting in intact ABP that precipitates to form amyloid
28
Q

What is the link between amyloid processing and familial AD?

A

Familial AD (2%) correlates with mutations in APP- increase the proportion of AB42

29
Q

Describe the structure of y-secretase

A

Complex enzyme comprising 4 components, PS1/PS2, nicastrin, Aph-1, Pen-2

30
Q

What is the role of presenilin in y-secretase?

A

Is the catalytic subunit- member of the intramembrane cleaving proteases

31
Q

Why are drugs such as Semagestat thought to not work for AD by inhibiting y-secretase?

A

Y-secretase has several substrates such as Notch, reducing this worsens the disease

32
Q

What is BACE and why is its inhibition though to be a potential AD treatment?

A

BACE is one of the molecules which cleaves APP- by inhibiting this enzyme, it is though the build-up of amyloid could be prevented

33
Q

What is the tau hypothesis of AD?

A

Neurofibrillary tangles contain paired helical filaments which are normally phosphorylated. Hyperphosphorylated tau has more phosphates (8-9) than normal (2-3).
Healthy neuron has microtubules stabilised by tau. Hyperphosphorylated tau cannot do this and causes them to dissociate with microtubules.

34
Q

What are the three hypotheses of how tau spreads in AD?

A
  1. Particles released by dying cell and taken up by adjacent cells
  2. Particles actively excreted by one cell then taken up by adjacent cell
  3. Particles “transmitted” through neurotransmission-like manner
35
Q

What is ApoE and how is it implicated in AD?

A

Is a glycoprotein involved in cholesterol metabolism; has different alleles.
E4 allele found in 40% of AD patients; E2 seems to protect against AD

36
Q

What is the strategy for ApoE drug therapy?

A

Look to convert ApoE4 -> ApoE3 by preventing arginine interactions in the structure

37
Q

Describe the pathology of AD

A
  1. AB deposition preceeds neurofibrillary tangles and neuritic changes start in frontal lobes, hippocampus and limbic system
  2. Neurofibrillary tangles and neuritic degeneration start in medial temporal lobes
38
Q

What are the three pillars of drug development?

A
  1. Drug needs to be at site of action over desired time period
  2. Drug needs to bind to target
  3. Drug needs to elicit desired effect
39
Q

Why have therapeutic approaches against tau all failed?

A

Approaches so far have focussed on hyperphosphorylation- too many sites to tackle
Approaches focusing on tau aggregation have failed

40
Q

What is the micro-glial hypothesis in AD?

A

TREM2- AD risk factor almost exclusively expressed in glial cells. Activated microglia associated with plaques- aberrant microglial innate immune response could contribute to disease progression.

41
Q

What are microglial mediated antibodies and what do they do?

A

Developed to lead microglia to the plaques and remove them

42
Q

What are direct resolution antibodies?

A

Supposed to break up plaques

43
Q

What is the peripheral sink model for antibodies?

A

Bind with AB in blood and remove AB before it gets to CFF

44
Q

What is the theory behind antibodies that block toxic oligomers?

A

Supposed to directly bind antibodies to toxic AB oligomers

45
Q

What biomarkers can be used to identify AD?

A

MRI; PET imaging; soluable markers can measure phosphorylated tau

Molecular Pharmacology (6 decks)

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