Cholesterol in NDDs

Question 1

What is the primary source of cholesterol?

Answer 1

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

Question 2

What is LDL?

Answer 2

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

Question 3

What is HDL?

Answer 3

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

Question 4

Which organ is richest w/ cholesterol?

Answer 4

Brain (~25%)

Question 5

Role of cholesterol in nervous sys.?

Answer 5

• 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

Question 6

Components of cholestrol?

Answer 6

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

Question 7

What is 70% of brains choelstrol associated with?

Answer 7

Myelin

Question 8

How does cholestrol play a role in the synapse?

Answer 8

• 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

Question 9

Does chol. cross the BBB?

Answer 9

No, so brain makes its own

Question 10

What is the biggest contributor to brain chol. homeostasis?

Answer 10

“de novo” synthesis

Question 11

What is chol. secreted as in the brain?

Answer 11

24-hydroxycholestrol

Question 12

Is brain cholestrol stable?

Answer 12

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

Question 13

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

Answer 13

Hydroxy-methyl glutaryl CoA reductase (HMGR)

Question 14

What does the mevalonate pathway also produce?

Answer 14

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

Question 15

What can cholestrol be made into?

Answer 15

Neurosteroids and oxysterols

Question 16

What inhibits HMGR?

Answer 16

Statins

Question 17

What does HMGR do?

Answer 17

Convert HMG-CoA into Mevalonate

Question 18

When is synthesis of cholestrol highest in CNS?

Answer 18

After birth due to highest myelination

Question 19

Which cell makes most of the chol. when young?

Answer 19

Neurons, as astrocytes have not been differntiated yet

Neuron chol. production is reduced in adulthood

Question 20

What is the transporter protein found on astrocytes?

Answer 20

ABCA1

Question 21

What is APOE?

Answer 21

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

Question 22

Do Astrocyte lipoprotein cross the bbb?

Answer 22

No

Some excreted in CSF

Question 23

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

Answer 23

Yes.

Question 24

What metabolizes 24HC?

Answer 24

Excreted into bile by liver

Question 25

What determines APOE function?

Answer 25

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

Question 26

Is aPOE4 lipidated?

Answer 26

No, thus has poor chol. efflux

Question 27

is APOE2 lipidated?

Answer 27

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

Question 28

What is the strongest genetic risk factor for AD?

Answer 28

APOE4

Question 29

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

Answer 29

Chol. metabolism; immunity/inflammation; endosomal vesicle recycling

Question 30

Effect of APOE on A-beta clearance?

Answer 30

* 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 ## Footnote Slide 26

Question 31

Can APOE3 inhibit tau hyperphosphorylation?

Answer 31

Yes ## Footnote APOE4 can stimulate it

Question 32

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

Answer 32

* 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)

Question 33

___ dysfunction seems to be a factor in EOAD and LOAD

Answer 33

Mitochondrial dysfunction

Question 34

How does APOE4 affect mitochondria?

Answer 34

* Increases dysfunction * APOE4 carriers have more oxidative mito dysfunction * APOE4 binds to subunits of mitochondria respiratory complexes

Question 35

Is APOE4 associated with overactive inflammation?

Answer 35

Yes

Question 36

Chol. depletion leads to:

Answer 36

* 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**

Question 37

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

Answer 37

No, whats more important is intracellular cholestrol distribution

Question 38

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

Answer 38

* Localization of APP proteolytic enzymes to lipid rafts * APP endocytosis * APP trafficking * Direct regulation of cleavaeg enzymes activity

Question 39

How does cholestrol **modulate secretase** activity?

Answer 39

* 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 activit**y, and reduces a-beta

Question 40

Does cholestrol promote endocytosis?

Answer 40

Yes, it promotoes endocytosis of APP and BACE1, thus decreasing non-amyloidogenic activity (since this occurs at cell surface) ## Footnote slide 41

Question 41

What does statin do?

Answer 41

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

Question 42

What are the confounding factors w/ statins in AD?

Answer 42

* Different hydrophobicities, thus some cross BBb , some dont * Stages inAD * Pleitropic metabolic effects