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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
What are the two different processes of getting rid of Amyloid in the brain?
1. Degraded by proteases leading to clearance: Insulin degrading enzyme Neprilysin Matrix metalloprotreases Angiotensin converting enzymes 2. Removed by Microglia
26
the normal monomeric form of Amyloid can have an ______ fucntion
antioxidant Can also moduate metals in the brain
27
What are the abnromal fucntions of Amyloid?
Aggregation into amyloid Aggregation in oligomers Neurotoxic effects inflammation
28
Other than Amyloid what is the other neuropathologic elements in AD?
Neurofibrillary triangles (NT)
29
NTs are formed from what?
Tangles, composed of a hyperphosphorylated form of microtubule protein called tau
30
the hypophosphorylation causes tau to become ______ and aggregated into ____ (filaments of protein twisted together in pairs)
the hypophosphorylation causes tau to become insoluble and aggregated into NFTs
31
Neurofibrillary tangles are also associated with _____
tauopathies (frontotemporal dementia)
32
What does tau do under normal conditions?
tau is normally attaches to microtubules and allows struture movement and intracellular transport
33
What triggers tau to be released from microtubules
hyperphosphorylation, | results in abnormal cytoskeletal structure and inhibition of IC transport
34
What increases when tau is released from microtubules and what does this cause
INcreased oxidative stress in the neurons - causes cross-linking that further inhibits the degradation of NFTs by the cell
35
Literature suggests Amyloid beta comes before...
tau hyperphosphorylation
36
What are the contributing factors to AD?
Age Oxidative stress loss of normal neuronal metal homeostasis inflammation
37
'leakage' of moleclar intermediates from the mitochondrial electron transport chain can lead to
oxidative and nitrosative stress imbalance between generation and removal of radicals
38
Peroxynitrite and Hydroxyl radical are..
very dangerous compounds, will bind to things and irreversibly change it leading to oxidative damage
39
What are some sources of oxygen radicals in AD?
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
Metals can _____ free radicals
Metals can catalyse free radicals
41
Consquences of excessive oxygen radicals?
protein oxidation DNA oxidation and strand breaks Downstream effects include: Nerotoxic actions of latered lipids aggregated protein DNA damage
42
Biometals are?
copper, zinc, iron - ones with important enzymatic functions and so on...
43
High levels of copper and zinc are found in..
AD plaques
44
There is strong evidence of altered zinc and copper _______ in AD brain
metabolism
45
There are high levels of copper and zinc in AD brain ___
extracellular fluid
46
There can be up to a 50% decrease in ______ of affected regions in AD
neurons
47
metals are the main source of ___ ______ generation in the brain
free radical
48
Amyloid beta binds copper and zinc at several sites involving _____ and _______ AAs
Histidine and Tyrosine
49
Binding of metals by AB...
promotes the aggregation of the peptide copper induces formation of neurotoxic oligomers
50
Copper causes ____-_____ between AB monomers to form stable neurotoxic dimers
cross-linking
51
Amyloid deposits large amoutns of ____ and ___
copper and zinc
52
AB has binding sites for ____ and _____
copper and zinc
53
What are the sources of imflammation in AD?
Resting resident brain macrophaages (microglia) become activated infiltration of peripheral monocytes
54
What initiated inflammation in AD?
likley response to aggregated zmyloid response to degenerating synapses and neurons
55
What are the consquences of inflammation in AD?
release of neurotoxic cytokines Increased free radical production Further damage to neurons and synapses
56
Summary of AD characteristics?
loss of memory and higher brain function Brain atophy EC amyloid plaques IC nerofibrillary triangles Gliosis (activation of microglia)
57
Amyloid plaques are composed of...
Amyloid beta peptide
58
Amyloid is ___ under nromal light and ____/____ under polarised light when stain Congo red
Amyloid is redunder nromal light and Green/yellow under polarised light when stained Congo red

Molecule to Malady (36 decks)

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