Cholesterol in NDDs Flashcards
What is the primary source of cholesterol?
Liver (65-75%); food (25-35%)
What is LDL?
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
What is HDL?
High density cholesterol carry excess cholesterol in the blood back to liver
Which organ is richest w/ cholesterol?
Brain (~25%)
Role of cholesterol in nervous sys.?
- 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
Components of cholestrol?
Hydroxy group is polar and attracted ti ohosphate head of phospholipids; non-polar part attracted to hydrophobic tails in centre
What is 70% of brains choelstrol associated with?
Myelin
How does cholestrol play a role in the synapse?
- 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
Does chol. cross the BBB?
No, so brain makes its own
What is the biggest contributor to brain chol. homeostasis?
“de novo” synthesis
What is chol. secreted as in the brain?
24-hydroxycholestrol
Is brain cholestrol stable?
Yes, thus it can be stored. Half life around 0.5-1year
What is the rate limiting enyzme of the chol. synthesis pathway (mevalonate pathway)?
Hydroxy-methyl glutaryl CoA reductase (HMGR)
What does the mevalonate pathway also produce?
Non-sterol isoprenoids: FPP, GGPP, ubiquinone, dolichol (all of these are also important, so blocking this pathway to reduce chol. can be detrimental)
What can cholestrol be made into?
Neurosteroids and oxysterols
What inhibits HMGR?
Statins
What does HMGR do?
Convert HMG-CoA into Mevalonate
When is synthesis of cholestrol highest in CNS?
After birth due to highest myelination
Which cell makes most of the chol. when young?
Neurons, as astrocytes have not been differntiated yet
Neuron chol. production is reduced in adulthood
What is the transporter protein found on astrocytes?
ABCA1
What is APOE?
apoe is a ligand for LDLR receptors on neuron’s; bind to cholesterol and allow cholesterol. uptake by neurons
Do Astrocyte lipoprotein cross the bbb?
No
Some excreted in CSF
Does 24-hyodroxycholestrol (24HC) diffuse into circulation?
Yes.
What metabolizes 24HC?
Excreted into bile by liver
What determines APOE function?
Lipidation, as it exposes key amino acids involved in receptor binding
Is aPOE4 lipidated?
No, thus has poor chol. efflux
is APOE2 lipidated?
Yes, it is the most lipidated out of the 3 isoforms
What is the strongest genetic risk factor for AD?
APOE4
What have all the genetic loci that that have been associated with AD been involved in?
Chol. metabolism; immunity/inflammation; endosomal vesicle recycling
Effect of APOE on A-beta clearance?
- 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
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Can APOE3 inhibit tau hyperphosphorylation?
Yes
APOE4 can stimulate it
What are the a-beta indepednent ways APOE plays a role in AD?
- 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)
___ dysfunction seems to be a factor in EOAD and LOAD
Mitochondrial dysfunction
How does APOE4 affect mitochondria?
- Increases dysfunction
- APOE4 carriers have more oxidative mito dysfunction
- APOE4 binds to subunits of mitochondria respiratory complexes
Is APOE4 associated with overactive inflammation?
Yes
Chol. depletion leads to:
- 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
Is data supporting elevated cholestrol as a risk factor to AD consistent?
No, whats more important is intracellular cholestrol distribution
How does an increase in chol. favour amyloidogenic APP cleavage and a-beta production?
- Localization of APP proteolytic enzymes to lipid rafts
- APP endocytosis
- APP trafficking
- Direct regulation of cleavaeg enzymes activity
How does cholestrol modulate secretase activity?
- 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
Does cholestrol promote endocytosis?
Yes, it promotoes endocytosis of APP and BACE1, thus decreasing non-amyloidogenic activity (since this occurs at cell surface)
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What does statin do?
- Lowers LDL cholestrol and triglycerides
- Increase HDL chol.
- Reduce risk of stroke/heart attack
*No consensus in effiacy with AD
What are the confounding factors w/ statins in AD?
- Different hydrophobicities, thus some cross BBb , some dont
- Stages inAD
- Pleitropic metabolic effects
