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Molecule to Malady > Lecture 20 > Flashcards

Lecture 20 Flashcards

Alzheimer's Disease part 1

1
Q

First doccumeneted case of AD was in…

A

1906

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2
Q

____ MILLIONS PATEINTA ARE ESTIMATED TO HAVE ad

A

35.6

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3
Q

__ million patients by 2050

A

114 million

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4
Q

Gross Atrophy (shrinage) of the brain is characters but not _____ to AD

A

specific

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5
Q 
True or False
Extracellular Neuritic (amylooid) plaques are specific to AD
A

True

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6
Q

Other general Neuropathology of AD:

Intraneuraonal ______ tangles

Cerebrovascular ______ (CAA)

Activation of ____ , hypertrophy of _________

Degree of dementia/memory impairment - loss of _______

Loss of _________as disease progresses

A

Intraneuraonal Neurofibrillary tangles

Cerebrovascular Amyloid

Activation of microglia, hypertrophy of astrocytes

Degree of dementia/memory impairment - loss of synapses (correlated)

Loss of neurons as disease progresses

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7
Q

When stained Amyloid plaques appear..

A

dark and circular - throughout the grey matter

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8
Q

Amyloid plaques:

Aggregated amyloid beta _-____ (forming fibrils)

______ -___birefringence with congo red stain

many _________ beta components in plaques

High concentration of _____ions

Readily ____ ___ in brain

May be “end point” of _____pathway

Assoc. with ________ inflammation

A

Aggregated amyloid beta peptide (forming fibrils)

Green-red birefringence with congo red stain

many non-amyloid beta components in plaques
- a “sink”, very sticky

High concentrationof metal ions

Readily turned over in brain

May be “end point” of amyloid pathway

Assoc. with secondary inflammation

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9
Q

What is amyloid?

A

Starch-like material

Rich beta-sheet protein structure

Can have fibrils in it

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10
Q

How is Amyloid formed?

A

Not specific for a primary protein sequences

(Amyloid can form from other proteins in different tissues)

  1. Proteins begin as unstructured monomers (little helix and sheet structure)
  2. with Inc. concentration or under certain envirnomental conditions, B-she1et structure increases
  3. Monomers begin to form parallel B-Sheet structures (protofibril_

protofibrils mature into fibrils and form plaques

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11
Q

Monomeric AB peptide can aggregate to form fibrillar _______

A

Monomeric AB peptide can aggregate to form fibrillar amyloid

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12
Q

Monomeric AB can form oligomeric (a molecular complex that consists of a few monomer units) species - consisting of 2-10+ monomers packed closely together

Oligomers may become cross-linked by specific amino-acid modificaions - what does this do for the oligomer?

A

Increases stability

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13
Q

Oligomers are thought to be the primary ___ form of AB

A

toxic

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14
Q

How is amyloid beta peptide produced?

A
  1. Cleavage of larger amyloid Precursor protein (APP) by ‘secretases’ (proteases) at the membrane of grey matter in the brain
  2. Amyloid beta (AB) is released into the ECS (can be recycled)
  3. Amyloid deposits form between cells
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15
Q

Specifically the cleavage is performed by what?

A

beta secretase and then gamma secretase

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16
Q

true or False

APP can also be cleaved by a-secretase at a different site which prevents AB from forming

A

true

The remaining APP can be released as soluble APP

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17
Q

AB peptide is cut from a part of the APP inside or outside the cell?

A

outside the cell

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18
Q

which enzyme intially cuts APP?

A

BACE 1

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19
Q

APP is an integral membrane protein concentrated at _______ in the brain

A

synapses

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20
Q

Gene for APP is located on chromosome __

A

21

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21
Q

APP is complex, it have complex processing, what are some activities is has been described as having a part in?

A

Growth Promotion
reglation of synaptic function
metal homeostasis
Cell signalling

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22
Q

Which enzymes in the brain can degrade the amyloid peptide?

A

Insulin degrading enzyme

Neprilysin

Matrix metalloprotreases

Angiotensin converting enzymes

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23
Q

Reduction in ______activity has been observed in AD brain

A

Reduction in protease activity has been observed in AD brain

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24
Q

______can also remove amyloid, especially aggregated peptide and plaques

A

Microglia can also remove amyloid, especially aggregated peptide and plaques

25
Q

What are the two different processes of getting rid of Amyloid in the brain?

A
  1. Degraded by proteases leading to clearance:

Insulin degrading enzyme

Neprilysin

Matrix metalloprotreases

Angiotensin converting enzymes

  1. Removed by Microglia
26
Q

the normal monomeric form of Amyloid can have an ______ fucntion

A

antioxidant

Can also moduate metals in the brain

27
Q

What are the abnromal fucntions of Amyloid?

A

Aggregation into amyloid

Aggregation in oligomers

Neurotoxic effects

inflammation

28
Q

Other than Amyloid what is the other neuropathologic elements in AD?

A

Neurofibrillary triangles (NT)

29
Q

NTs are formed from what?

A

Tangles, composed of a hyperphosphorylated form of microtubule protein called tau

30
Q

the hypophosphorylation causes tau to become ______ and aggregated into ____ (filaments of protein twisted together in pairs)

A

the hypophosphorylation causes tau to become insoluble and aggregated into NFTs

31
Q

Neurofibrillary tangles are also associated with _____

A

tauopathies (frontotemporal dementia)

32
Q

What does tau do under normal conditions?

A

tau is normally attaches to microtubules and allows struture movement and intracellular transport

33
Q

What triggers tau to be released from microtubules

A

hyperphosphorylation,

results in abnormal cytoskeletal structure and inhibition of IC transport

34
Q

What increases when tau is released from microtubules and what does this cause

A

INcreased oxidative stress in the neurons - causes cross-linking that further inhibits the degradation of NFTs by the cell

35
Q

Literature suggests Amyloid beta comes before…

A

tau hyperphosphorylation

36
Q

What are the contributing factors to AD?

A

Age
Oxidative stress
loss of normal neuronal metal homeostasis
inflammation

37
Q

‘leakage’ of moleclar intermediates from the mitochondrial electron transport chain can lead to

A

oxidative and nitrosative stress

imbalance between generation and removal of radicals

38
Q

Peroxynitrite and Hydroxyl radical are..

A

very dangerous compounds, will bind to things and irreversibly change it leading to oxidative damage

39
Q

What are some sources of oxygen radicals in AD?

A

Mitochondria

Brain has high oxygen consumption and low antioxidant levels

Non-dividing cells build up oxidatively damaged molecules

amyloid beta can induce radicals

metals

inflammation

40
Q

Metals can _____ free radicals

A

Metals can catalyse free radicals

41
Q

Consquences of excessive oxygen radicals?

A

protein oxidation

DNA oxidation and strand breaks

Downstream effects include:

Nerotoxic actions of latered lipids

aggregated protein

DNA damage

42
Q

Biometals are?

A

copper, zinc, iron - ones with important enzymatic functions and so on…

43
Q

High levels of copper and zinc are found in..

A

AD plaques

44
Q

There is strong evidence of altered zinc and copper _______ in AD brain

A

metabolism

45
Q

There are high levels of copper and zinc in AD brain ___

A

extracellular fluid

46
Q

There can be up to a 50% decrease in ______ of affected regions in AD

A

neurons

47
Q

metals are the main source of ___ ______ generation in the brain

A

free radical

48
Q

Amyloid beta binds copper and zinc at several sites involving _____ and _______ AAs

A

Histidine and Tyrosine

49
Q

Binding of metals by AB…

A

promotes the aggregation of the peptide

copper induces formation of neurotoxic oligomers

50
Q

Copper causes ____-_____ between AB monomers to form stable neurotoxic dimers

A

cross-linking

51
Q

Amyloid deposits large amoutns of ____ and ___

A

copper and zinc

52
Q

AB has binding sites for ____ and _____

A

copper and zinc

53
Q

What are the sources of imflammation in AD?

A

Resting resident brain macrophaages (microglia) become activated

infiltration of peripheral monocytes

54
Q

What initiated inflammation in AD?

A

likley response to aggregated zmyloid

response to degenerating synapses and neurons

55
Q

What are the consquences of inflammation in AD?

A

release of neurotoxic cytokines

Increased free radical production

Further damage to neurons and synapses

56
Q

Summary of AD characteristics?

A

loss of memory and higher brain function

Brain atophy

EC amyloid plaques

IC nerofibrillary triangles

Gliosis (activation of microglia)

57
Q

Amyloid plaques are composed of…

A

Amyloid beta peptide

58
Q

Amyloid is ___ under nromal light and ____/____ under polarised light when stain Congo red

A

Amyloid is redunder nromal light and Green/yellow under polarised light when stained Congo red

Molecule to Malady (36 decks)

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