21: cholesterol

Question 1

cholesterol in brain %? what form? other derivatives?

Answer 1

brain contains 2-5% body mass, but 35% total body cholesterol. predominantly unesterified aka free cholesterol. only small amounts of cholesterol esters. other hydroxylated derivatives like 24 or 27 hydroxychol.

Question 2

cholesterol and BBB? excess cholesterol?

Answer 2

doesn’t readily cross BBB. so if you have chol in brain, it was made there. excess chol excreted from brain as 24 - hydroxycholesterol, synthesized by cholesterol 24 - hydroxylase

Question 3

cholesterol 24 hydroxylase: expressed where? not where?

Answer 3

only in a small population of neurons in brain: pyramidal cells of cortex, purkinje cells of cerebellum. not in glial cells.

Question 4

lipoproteins in CNS?

Answer 4

are HDL sized, no LDL in CNS. unesterified cholesterol mostly.

Question 5

in brain: CNS separated from plasma by? this means?

Answer 5

BBB so plasma lipoproteins like LDL can’t enter brain from plasma = all CNS cholesterol is made within the CNS

Question 6

which cells synthesize cholesterol?

Answer 6

all cells: neurons and glial

Question 7

major protein in CNS lipoproteins is? synthesized and secreted by?

Answer 7

apo E: synthesized/secreted by glial cells, NOT NEURONS

Question 8

apo E isoforms: what proteins?

Answer 8

E2 = cys + cys at 112 and 158. E3 = cys, arg. E4 = two arg

Question 9

E3 vs. E4 and mechanisms of AD? (4)

Answer 9

E3 promotes axonal growth/repair, E4 doesn’t. E4 has defective lipidation. E3 forms complex with AB to enhance degradation, E4 doesn’t. E3 protects from apoptosis more than E4.

Question 10

statins as treatment for AD? how?

Answer 10

some studies show it can reduce/delay AD. promote a secretase cleavage of APP = less AB. also some anti inflammatory effects

Question 11

bexarotene: what? effect?

Answer 11

retinoid X receptor agonist, regulates cholesterol metabolism. increases apo E synthesis and thus increases LpE secretion by astrocytes

Question 12

bexarotene conclusion: increases? reduces? improves?

Answer 12

increases apoE and LpE. reduces AB and plaques. improves cognition and memory.

Question 13

bexarotene not effective in?

Answer 13

not effective in Apo E KO mice, so LpE probably involved in the beneficial effect

Question 14

Niemann Pick Type C disease: what inheritance? what is it? what features?

Answer 14

inherited autosomal recessive. neurodegeneration disorder that results in ataxia, seizures, weight loss, death.

Question 15

npc 1 -/- mice: cerebellum?

Answer 15

purkinje cell degeneration

Question 16

npc1 protein? 2?

Answer 16

transmembrane protein, limiting membrane of lysosomes. larger. 2: smaller and soluble in lumen of lysosomes.

Question 17

NPC1 and 2: expression? main action?

Answer 17

expressed in all cells, aka neurons and glial. cholesterol binding proteins

Question 18

elimination of NPC1 only in neurons causes? conclusion?

Answer 18

causes the neurodegneration. this means the phenotype is due to lack of NPC1 in neurons, not glia

Question 19

current therapy for NPC disease?

Answer 19

no effective treatment but cyclodextrin reduces neurodegen in mice: cholesterol sequestring agent. use in low doses like 0.1 mM

Question 20

smith lemli optiz syndrome: what?

Answer 20

severe neurological disorder caused by genetic defect in final enzyme of cholesterol biosynth. pathway

Question 21

smith lemli optiz syndrome: characteristics?

Answer 21

defect in 7 dehydrocholesterol reductase = impaired chol synthesis. polydactylyl, syndactylyl, cleft palate, holoprosencephaly, neurological impairment, premature death

Question 22

smith lemli optiz syndrome fibroblasts: what do you see? causes of SLOS?

Answer 22

low cholesterol, high 7 DHC. developmental problems caused probably by 7DHC cholesterol, not chol deficiency