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NEURO 411 > Cholesterol in NDDs > Flashcards

Cholesterol in NDDs Flashcards

1
Q

What is the primary source of cholesterol?

A

Liver (65-75%); food (25-35%)

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2
Q

What is LDL?

A

low-density lipoprotein are bad cause they carry dietary and endogenous cholesterol to peripheral tissues, they can build up in the artery wall and narrow them

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3
Q

What is HDL?

A

High density cholesterol carry excess cholesterol in the blood back to liver

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4
Q

Which organ is richest w/ cholesterol?

A

Brain (~25%)

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5
Q

Role of cholesterol in nervous sys.?

A
  • Major component of mem.
  • Plays a role in synaptogensisi and neuronal plasticity
  • Plays a role in NT release at synapse
  • Organizes signal transduction events in lipid rafts
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6
Q

Components of cholestrol?

A

Hydroxy group is polar and attracted ti ohosphate head of phospholipids; non-polar part attracted to hydrophobic tails in centre

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7
Q

What is 70% of brains choelstrol associated with?

A

Myelin

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8
Q

How does cholestrol play a role in the synapse?

A
  • Essential for synaptic vesicle biogensis
  • Chol. is a component of syn. vesicles
  • Chol. supports intrinsic negative curvature of mem. during fusion
  • Chol. favours mem. fusion
    * Chol. is pivotal for NT release
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9
Q

Does chol. cross the BBB?

A

No, so brain makes its own

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10
Q

What is the biggest contributor to brain chol. homeostasis?

A

“de novo” synthesis

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11
Q

What is chol. secreted as in the brain?

A

24-hydroxycholestrol

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12
Q

Is brain cholestrol stable?

A

Yes, thus it can be stored. Half life around 0.5-1year

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13
Q

What is the rate limiting enyzme of the chol. synthesis pathway (mevalonate pathway)?

A

Hydroxy-methyl glutaryl CoA reductase (HMGR)

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14
Q

What does the mevalonate pathway also produce?

A

Non-sterol isoprenoids: FPP, GGPP, ubiquinone, dolichol (all of these are also important, so blocking this pathway to reduce chol. can be detrimental)

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15
Q

What can cholestrol be made into?

A

Neurosteroids and oxysterols

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16
Q

What inhibits HMGR?

A

Statins

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17
Q

What does HMGR do?

A

Convert HMG-CoA into Mevalonate

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18
Q

When is synthesis of cholestrol highest in CNS?

A

After birth due to highest myelination

19
Q

Which cell makes most of the chol. when young?

A

Neurons, as astrocytes have not been differntiated yet

Neuron chol. production is reduced in adulthood

20
Q

What is the transporter protein found on astrocytes?

A

ABCA1

21
Q

What is APOE?

A

apoe is a ligand for LDLR receptors on neuron’s; bind to cholesterol and allow cholesterol. uptake by neurons

22
Q

Do Astrocyte lipoprotein cross the bbb?

A

No

Some excreted in CSF

23
Q

Does 24-hyodroxycholestrol (24HC) diffuse into circulation?

A

Yes.

24
Q

What metabolizes 24HC?

A

Excreted into bile by liver

25
Q

What determines APOE function?

A

Lipidation, as it exposes key amino acids involved in receptor binding

26
Q

Is aPOE4 lipidated?

A

No, thus has poor chol. efflux

27
Q

is APOE2 lipidated?

A

Yes, it is the most lipidated out of the 3 isoforms

28
Q

What is the strongest genetic risk factor for AD?

A

APOE4

29
Q

What have all the genetic loci that that have been associated with AD been involved in?

A

Chol. metabolism; immunity/inflammation; endosomal vesicle recycling

30
Q

Effect of APOE on A-beta clearance?

A
  • Lipidated APOE -> Binds to a-beta and transports within CNS
  • Faciliattes proteolytic degreadation (E2>E3>E4)
  • APOE can facilitate uptake and A-beta degradation by glial cells (E2>E3>E4)
  • APOE allows A-beta to cross BBB

Slide 26

31
Q

Can APOE3 inhibit tau hyperphosphorylation?

A

Yes

APOE4 can stimulate it

32
Q

What are the a-beta indepednent ways APOE plays a role in AD?

A
  • Tau (APOE4 bad)
  • Synapsis (APOE4 -> fewer/shorter dendritic spines)
  • Cognition- Affects LTP (E4>E3>E2)
  • Lipid metabolism
  • Neurotoxicity (APOE4 N-terminal is toxic)
  • BBB dysfunction (more permability in APOE4)
33
Q

___ dysfunction seems to be a factor in EOAD and LOAD

A

Mitochondrial dysfunction

34
Q

How does APOE4 affect mitochondria?

A
  • Increases dysfunction
  • APOE4 carriers have more oxidative mito dysfunction
  • APOE4 binds to subunits of mitochondria respiratory complexes
35
Q

Is APOE4 associated with overactive inflammation?

A

Yes

36
Q

Chol. depletion leads to:

A
  • Impaired synaptic vesicle exocytosis
  • reduction in NT release
  • Compromised synaptic recycling
  • Blockage and reudction of AMPArs, impair LTP,LTD
  • Depletion in post-syn can lead to detachment of important signalling molecules
  • Syanpse transmission is disturbed
37
Q

Is data supporting elevated cholestrol as a risk factor to AD consistent?

A

No, whats more important is intracellular cholestrol distribution

38
Q

How does an increase in chol. favour amyloidogenic APP cleavage and a-beta production?

A
  • Localization of APP proteolytic enzymes to lipid rafts
  • APP endocytosis
  • APP trafficking
  • Direct regulation of cleavaeg enzymes activity
39
Q

How does cholestrol modulate secretase activity?

A
  • By creating lipid rafts where APP is cleaved into a-beta by BACE1
  • Outside of rafts –> APP undergoes alpha-cleavage (non-amyloidogenic)
  • Chol. depletion: decreases BACE1 and y-secretase activity, and reduces a-beta
40
Q

Does cholestrol promote endocytosis?

A

Yes, it promotoes endocytosis of APP and BACE1, thus decreasing non-amyloidogenic activity (since this occurs at cell surface)

slide 41

41
Q

What does statin do?

A
  • Lowers LDL cholestrol and triglycerides
  • Increase HDL chol.
  • Reduce risk of stroke/heart attack
    *No consensus in effiacy with AD
42
Q

What are the confounding factors w/ statins in AD?

A
  • Different hydrophobicities, thus some cross BBb , some dont
  • Stages inAD
  • Pleitropic metabolic effects
43
Q
A

NEURO 411 (12 decks)

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