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physiology and pharma > L15 - alzheimers > Flashcards

L15 - alzheimers Flashcards

1
Q

what are the two major treatments for alzheimers

A

anticholinesterases
NMDA receptor antagonists

only symptom treating, as the cause of disease is unknown

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2
Q

describe the process of formation of senile plaques (ß amyloid plaques)

A
  • ß amyloid precursor protein is present in the fatty membranes that surround neurones
  • Normally, alpha and gamma secretases cleave this protein (within the ß amyloid sequence) which doesn’t produce the ß amyloid protein

However, a disorder in processing this amyloid precursor protein leads to the formation and accumulation of ß amyloid protein in the extracellular space.
This is an adhesive molecule so over time the proteins come together to form a plaque

It is not understood why some of the ß amyloid is internalised and why some is in extracellular space

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3
Q

where is the ß amyloid precursor protein usually found

A

in fatty membranes surrounding neurones

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4
Q

what happpens to the ß amyloid precursor protein in the normal, healthy situation

A

alpha and gamma secretases cleave it within the ß amyloid sequence, so that the ß amyloid protein isnt formed

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5
Q

what cleaves the ß amyloid precursor protein

A

alpha and gamma secretases

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6
Q

why do ß amyloid proteins form plaques?

A

they are adhesive molecules and so they ‘stick’ together

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7
Q

do ß amyloid plaques only form in alzheimers patients?

A

no they naturally form with age, but it happens to a much larger extent in AD patients

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8
Q

how is ß amyloid plaque formation in healthy individuals usually prevented?

A

by surface endocytosis of the ß amyloid proteins to prevent accumulation in extracellular space

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9
Q

what could be the cause of this abnormal ß amyloid precursor protein processing

A
  1. genetic -> more than 50 mutations in APP gene can cause early onset AD. these mutations either increase ß amyloid protein production or produce longer, stickier versions of it
  2. environmental -> HBP and high cholesterol seem to increase risk of AD
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10
Q

what can mutations in the ß amyloid precursor protein gene lead to? and how does this relate to AD

A

either

  • increased production of ß amyloid protein
  • production of a longer, stickier ß amyloid protein
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11
Q

what environmental factors correlate with increased risk of AD and why?

A

HBP
high cholesterol levels

unknown whether this causes increased ß amyloid protein production or increased deposition in extracellular space

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12
Q

why are amyloid plaques harmful?

A

→ inflammation occurs around the plaques which is toxic to neighbouring neurones, leads to their destruction
this impairs communication between neurones (via damage to dendrites and axons) as well as neurones being surrounded by dead neurones

→ can lead to excitotoxicity by: increasing vulnerability of neurones to glutamate via activation of NMDA receptors
(NMDA activation can also affect tau expression and function)

->cause changes in synaptic ACh transmission

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13
Q

what is the significance of tau proteins

A

tau proteins bind to microtubules and regulate their stability

they are important in maintenance of neuronal activity

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14
Q

how is the normal fucntioning of tau proteins altered in AD

A
  1. in AD, there is presence of abnormally phosphorylated tau proteins which causes them to tangle
  2. they are then unable to bind and regulate microtubbule stability
  3. this can lead to collapse of microtubules and destruction of neurones
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15
Q

describe neurofibrillary tangles

A
  1. made up of tangles of abnormally phosphorylated tau proteins which form filaments

density of NFTs in brain is directly related to severity of alzheimers

unclear why tangles form

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16
Q

comment on genetic influence of Tau tangling

A

there are genetic forms of tau that are more likely to form tangles.

supports genetic influence in AD

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17
Q

what is importannt to note about ß amyloid plaques in AD

A

deposition of ß amyloid plaques alone is not sufficient for the neuropathy seen in AD, because
- plaques are seen in normal ageing brain and some elderly patients with them experience no cognitive impairment

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18
Q

there is some evidence that the neurotoxic environment created by amyloid plaques can result in NFTs

A

there is some evidence that the neurotoxic environment created by amyloid plaques can result in NFTs

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19
Q

describe cholinergic degeneration in AD

A

degeneration of neurones in the nucleus basalis meynert (the origin of major cholinergic projections to the neocortex) has been shown to occur in early AD

AD involves substantial loss of transmission in cholinergic system (neurones and loss of choline transferase required for ACh synthesis)

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20
Q

what effects on the cholinergic system have been observed in AD

A
  1. loss in cholinergic transmission through degeneration of neurones in the nucleus basalis meynert (the origin of major cholinergic projections to the neocortex)
  2. loss of choline acetyltransferase (needed for ACh synthesis)
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21
Q

what is the nucleus basalis meynert

A

(the origin of major cholinergic projections to the neocortex)

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22
Q

what are the brain regions most affected by cholinergic degeneration in AD

A

cortex
hippocampus
basal forebrain (severly)
ventral striatum

these are regions we would expect to find plaques and NFTs

23
Q

explain how cholinergic degradation leads to symptoms of alzheimers

A

cholinergic system is important in cognitive processes including learning and memory

severe degeneration in the basal forbrain nuclei means diminished output from the hippocampus and neocortex (both major sites inolved in cognition and memory)

24
Q

describe mechanism of anti-cholinesterases as treatment for AD

A
  1. reduce breakdown of ACh by acetylcholinesterase, increasing [ACh] in cleft
  2. this enhances neurotransmission and ability to activate receptors on alive neurones
25
Q

does Anticholinesterase treatment (increasing [ACh] in cleft) cause receptor sensitisation?

A

No

26
Q

AD treatment with anti-cholinesterases is only effective for 1-3 years, why?

A

because it doesnt alter disease progression, neurones continue to die until eventually increasing [ACh] doesnt help as there are no functioning cholinergic neurones

27
Q

describe evidence for role of AChE in pathogenesis of AD?

A
  1. there is a small structural motif within AChE that interacts with deposited B amyloid proteins promoting fibril formation
  2. AChE staining around B amyloid plaques is very storng
28
Q

examples of an AChE inhibitor

A

donepezil

rivastigmine
galantamine

29
Q

describe features of the AChE inhibitor donepezil

A

high selectivity for CNS AChE (less peripheral side effects)
upregulates nAChRs in cortical neurones

30
Q

side effects of donepezil (AChE inhibitor)

A

GI disturbances
loss of appetite
muscle cramps

31
Q

explain the influence of the glutamatergic system in AD

A

glutamatergic excitatory system critical in brain for learning and memory

glutamate excitotoxicity (via /NMDA receptor activation) can cause neuronal cell death

32
Q

define glutamate excitotoxicity in terms of AD

A

inapropriately sustained glutamate mediated activation of NMDA receptors leading to neuronal cell death

33
Q

what effect do B amyloid plaques have on the glutamatergic system

A

there is evidence that:
- B amyloid plaques can increase vulnerability of neurones to glutamate, leading to glutamate excitotoxicity via interaction with NMDA receptors

34
Q

how is Tau affected by the glutamatergic system?

A

NMDA receptor activation can affect tau expression and function

35
Q

what drugs can target glutamatergic system to treat AD

A

NMDA receptor antagonists eg memantime - a non competitive NMDA channel blocker

36
Q

describe function of NMDA receptor antagonists eg memantime

A
  1. block the NMDA receptor preventing excitotoxicity (and especially destruction of of cholinergic neurones) - blocks low, weak activity associated with tonic levels of glutamate. high levels can still activate the receptor
  2. at low concs it can promote synaptic plasticity
37
Q

what is synaptic plasticity

A

ability of synapses to strengthen or weaken

38
Q

memantine and donezepil often given in combination

A
39
Q

side effects of memantine

A

usually well tolerated

dizziness
confusion
headaches

40
Q

what other receptors does memantine act on and what effect does this have in AD

A

5-HT3 receptor antagonist, whihch may have beneficial effect on cognition and memory

41
Q

explain M1 muscarinic agonists in AD treatment

A

M1 receptor activation does the following in AD

  • increases soluble APP release via increase in alpha secretase (less amyloid formation)
  • decreases tau phosphorylation
  • alleviates cognitive deficits in cotex and hippocampus in mouse models of AD
  • aids cholinergic defecit (via receptor activation instead of ACh)
42
Q

what effect does M1 activation in AD have on tau

A

decreases its phosphorylation

43
Q

what effect does M1 activation in AD have on plaque formation

A

increases alpha secretase levels and so increases release of soluble amyloid precursor protein instead of B amyloid protein

44
Q

how are M1 receptors affected in AD

A

-coupling of M1 receptors to G proteins in neocortex is impaired (less effective receptor activation)

45
Q

how are M2 antagonists used in AD tretament

A

M2 antagonists reduce the negative feedback inhibiton of ACh release - leading to increased M1 receptor activation

46
Q

what evidence is there for the (2x a4) (3x B2) nAChR being neuroprotective?

A

in regions of brain with high levels of B amyloid, a4B2 receptor mediated cholinergic responses were impaired

47
Q

what evidence is there for the involvement of a7 nAChRs in AD

A
  • In regions of the brain that had high levels of ß amyloid, the cholinergic response by a7 receptors is impaired
  • Protects against toxicity of ß amyloid plaques
48
Q

what evidence is there for the significance of nicotine in AD

A
  • nicotine upregulates expression of nAChRs
  • in cultured neurones (with a7 / a4B2 receptors) nicotine prevents B amyloid induced apoptosis
  • other studies have shown nAChR activation results in increases B amyloid plaque mediated tau phosphorylation
49
Q

modulation of different cholinergic receptors might play different roles in AD pathology at different stages of the disease

A
50
Q

what are the limitations of current AD treatments

A
  • disease is progressive so treatments must adapt to differnet stages
  • no single model that can well mimic all stages of the disease
  • dont know the entire pathology / origin of the disease (so no disease modifying treatments have been developed)
51
Q

promising future AD treatments?

A

secretases

B amyloid antibodies

52
Q

what would an ideal disease modifying therapy target?

A

prevention of B amyloid formation (secretases etc)

prevent NFTs (prevention of tau phosphorylation) (kinase inhibitors)

decrease glutamate excitotoxicity

53
Q

symptoms of AD

A

amnesia -> loss of memory (short and long term)
aphasia -> simplified language use
apraxia

54
Q

AD can also cause other associated symptoms such as mood disorders, depression

A

treated with antidepressants, anxiolytics etc

physiology and pharma (18 decks)

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