NB3-2 - Biochemical Integrative Metabolism: Brain Metabolism

Question 1

Are neurons or glia more abundant in the nervous system?

Answer 1

Glia

Question 2

How much glucose does the brain require?

Answer 2

100g of glucose per day

Question 3

What percent of total body oxygen consumption (respiration) is used by the brain?

Answer 3

~20% at rest

Question 4

What are ketone bodies? Why does their synthesis occur? From what molecules are they synthesized?

Answer 4

The ketone bodies are ß-hydroxybutarate, acetoacetate, and their spontaneous breakdown product acetone. These molecules are formed from acetyl-CoA which is coming from the catabolism of fatty acids, lysine, and leucine. This is done during periods of prolonged fasting (>2 or 3 days) as a way to supply energy to tissues without having to burn up all available amino acids in gluconeogenesis.

Ketone bodies are crucial to brain metabolism during fasting because Acetyl-CoA and fatty acids cannot cross the BBB but ketone bodies can and brain cells can then convert them into acetyl-CoA

Question 5

Why are ketone bodies not enough to keep brain metabolism going? Why is glucose needed?

Answer 5

Ketone bodies can be broken down into acetyl-CoA which can be fed into the TCA cycle. However, to start the TCA cycle, OAA must also be present. OAA can only come from malate (via malate dehydrogenase) or pyruvate (via pyruvate carboxylase). Since TCA intermediates are constantly being removed from the cycle for use in other pathways, OAA must come from pyruvate which only comes from glycolysis. This is essentially why the brain really needs glucose.

Question 6

Describe how glucose gets from the blood into a neuron.

Answer 6

GLUT 1 transports it across the BBB

GLUT 3 transports it into the neurons

Question 7

How do ketone bodies get across the BBB?

Answer 7

The monocarboxylate transporter

Question 8

What are the major factors influencing whether or not CNS metabolism continues?

Answer 8

Glucose Supply

Oxygen Supply

Vitamin B1 (TPP) supply

Question 9

Answer 9

D

Question 10

List and describe the forms of thiamine deficiency. Which populations are most susceptible to this?

Answer 10

Wernicke-Korsakoff Syndrome and Beriberi are the two names for thiamine deficiency

Acute symptoms are mental confusion, ataxia, and opthalmoplegia (eye muscle paralysis). If the deficiency reaches the chronic stage then retrograde and/or anterograde amnesia can present, sometimes irreversibly.

Alcoholics and people living in cultures with a monocereal diet (ie - mostly white rice) are most at risk for developing a thiamine deficiency.

Question 11

List the key cofactors required in CNS metabolism and mention what type of reactions they take part in.

Answer 11

Vit B6 (PLP) is needed for decarboxylation reactions

Folate (B9) is needed for 1-carbon transfer reactions

Cobalamin (B12) is needed to regenrate methionine from homocysteine

Vit B1 (TPP) for PDH complex, α-KGDH, and BCAA DH

Question 12

Why would some hydrophobic drugs not pass the BBB as readily as expected?

Answer 12

Because they are bound to serum albumin which tries to keep them in the blood

Question 13

What types of molecules have dedicated BBB transporters?

Answer 13

The essential fatty acids and vitamins

Protein hormones (ie - insulin & GF)

Large Neutral Essential Amino Acids

Question 14

Which amino acids utilize the large neutral amino acid BBB transporter?

Answer 14

Phenylalanine, Valine, Tyrosine, Tryptophan, Isoleucine, Methionine, Histidine, Leucine, and L-DOPA

Question 15

How does PKU affect the brain? What other diseae has similar effects?

Answer 15

Phenylketonuria disallows the catabolism of phenylalanine. This leads to an accumulation of Phe that will outcompete the other large neutral amino acids for the BBB transporter which leads to an over abundance of Phe in the brain and a defecit of other amino acids.

Maple Syrup Urine disease has similar effects

Question 16

What types of amino acids are blocked from passing the BBB?

Answer 16

Ones that are themselves NTs

Question 17

Which catecholamine precursors can and cannot cross the BBB? Why is this important to consider when treating Parkinson’s disease?

Answer 17

Phenylalanine, tyrosine, and L-DOPA can all cross the BBB

Dopamine, NE, and E cannot

BBB endothelial cells contain DOPA decarboxylase which turns L-DOPA into Dopamine. Therefore, when treating Parkinson’s disease with L-DOPA a DOPA decarboxylase inhibitor must also be given so the DOPA can cross the BBB.

Question 18

Answer 18

C

Question 19

Why is lipid synthesis occuring most frequently in the CNS?

Answer 19

Neurotransmission involves rapid change in the membrane structure at the synapse due to abundant endo- and exocytosis occurring. Myelin resynthesis is also always occurring.

Question 20

Is multiple sclerosis genetic or environmental?

Answer 20

It is both, it is multifactorial

Question 21

What is a prion disease?

Answer 21

A disease caused by a prion which is a misfolded protein that can induce other proteins to also fold abnormally.

Question 22

What are the different names and forms of Mad Cow Disease?

Answer 22

In sheep it’s called Scrapie

In cattle it’s called Mad-Cow Disease or Bovine Spongiform Encephalopathy (BSE)

Its first appearance in humans was called Creutzfeldt-Jakob disease (CJD). When it crossed over from cows to humans in 1996 it was called new variant Creutzfeldt-Jakob Disease (vCJD)

Question 23

Describe the protein that becomes prionic in CJD both before and after it changes.

Answer 23

The normal prion protein (PrP) is a soluble glycoprotein (called PrP) that is anchored to the extracellular surface of neuronal membranes an has NO known function. It normally consists of only α-chains. The misfolded PrP, called PrPsc, has a ß-sheet conformation and is resistant to protease digestion. PrPsc is able to convert PrP to PrPsc catalytically just by coming into contact with it.

PrPsc is not soluble and it will aggregate other PrPsc to form plaques on neurons.

Question 24

Are the causes of CJD genetic or environmental? How is CJD diagnosed and what are its symptoms?

Answer 24

CJD is multifactorial (some genetic mutations put a patient at an increased risk but don’t guarantee pathology)

Most common symptoms are neurodegeneration, dementia, paralysis, and death. The only way to definitively diagnose CJD is upon autopsy.

Question 25

What protein is pathological in Alzheimers disease? How does it become this way and what happens once it has?

Answer 25

The amyloid-ß-peptide (Aß) is the protein from which the pathological peptide comes from. When Aß is proteolytically cleaved it’s usually busted up into non-toxic 40aa fragments. However, it can be erroneously cleaved into neurotoxic 42aa fragments. This form has a high ß-sheet content causing it to form aggregates and neurofibrillary tangles that are also found to contain hyperphosphorylated tau protein in neurons.