Cerebral Blood Flow and Metabolism

[STATs] Cerebral energy metabolism

STATs

• High rate of energy utilization

• ATP is generated through oxidative phosphorylation

• Uses 20% of resting blood oxygen

• Main fuel is blood glucose, very limited beta-oxidation

• Uses 50% of resting blood glucose

• Very little glycogen storage

1. Describe the relationship between CBF (cerebral blood flow) and CPP

2. What are the 3 mechanisms could contribute to CBF regulation

CBF regulations:

• Cerebral pressure autoregulation

• Flow-metabolism coupling

• Neurogenic regulation

Describe Cerebral pressure autoregulation

• Maintains?

• Mech

Cerebral pressure autoregulation

• maintains constant CBF in the ~70-150 mm Hg MAP range.

• Mech:

  • SMC + EC → "mechanical sensors" for CPP + Sheer Stress Sensor

    • Increases = Vasoconstriction → Increases CVR → Reduces CBF

Draw out the graph depicting MAP vs CBF

List the Flow-Metabolism Coupling

• How does Neuronal Activity lead to increasing CBF

  • Increased neuronal Metabolism?

• What is the Result of these things on Vasculature:

  • Low Blood/Tissue pO2:

  • Respiratory Acidosis/Alkalosis:

Flow-Metabolism Coupling

• Increased Neuronal Activity:

  • → increased metabolism → Increases CBF

    • → increases Extracellular K+ + adenosine → Vasodilation

• Increased Neuronal Metabolism:

  • → Increases CO2 → H+ → Vasodilation (increases CBF)

• Low Blood/Tissue pO2:

  • → Vasodialtion

    • B/C release of K+, adenosine and NO

• Respiratory Acidosis/Alkalosis:

  • Acidosis: → vasodilation

    • REMINDER: hypoventillation, high pCO2

  • Alkalosis: → Vasoconstriction

    • REMINDER: hyperventillation, low pCO2

Describe Neurogenic regulation of CBF

• Extrinsic vs Intrinsic

  • Mech of intrinsic?

• Extrinsic innervation

  • Para/sympathetic regulation of CBF in vessels outside of the brain parenchyma.

• Intrinsic Innervation:

  • CBF Regulation in vessels inside brain parenchyma.

    • via astrocyte end-feet (most likely)

    • Mech: K+ release/prostaglandins /NO synthesis

      • (due to increased [Ca2+]i) by the astrocyte.

1. Describe the Main utilization of ATP in the nervous system

2. Compare/Contrast Kinesins/Dyneins

ATP Utilization in NS:

• Maintaining ion gradients (e.g. Na-K ATPase).

• Biosynthetic pathways

• Axonal transport or organelles, proteins, mRNA

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Kinesins/Dyneins:

• Both: motor proteins that hydrolyze ATP to move cargo along the microtubules of axons.

• Kinesin:

  • Anterograde motility

  • Supply of new components by fast/slow axonal transport

• Dynein:

  • Retrograde:

  • Retrograde survival signaling and degradative traffic

Describe ATP generation from glucose in the brain

• Glut1 vs 3

• Additional source of energy?

• ATP generation from glucose in the brain

  • GLUT1: glucose → BBB

  • GLUT3: Glucose → Neurons

• Additional Source:

  • From Lactate produced by astrocytes from blood glucose or glycogen.

Explain how fats can be used to fuel the brain

Nonessential FA cannot pass BBB:

• Nonessential FA → oxidized in liver → acetyl-CoA converted to ketone bodies → circulation.

  • MCT1: Ketone →BBB

  • MCT2: Ketone → Neurons

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NOTE: MCT = Monocarboxylate transporter

Explain how these can occur → Energy deficiency in brain:

• Insufficient oxygen delivery

• Lack of energy sources

• Suboptimal energy generating pathways

Insufficient oxygen delivery

• Vasovagal syncope,

• head trauma

• stroke

• myocardial infarction

• pulmonary embolism

• high altitudes

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Lack of energy sources

• Hypoketotic hypoglycemia – b-oxidation deficiencies

• GLUT1 deficiency – low glucose uptake by the brain

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Suboptimal energy generating pathways

• Vitamin B1 deficiency

  • Wernicke-Korsakoff syndrome in chronic alcoholics (ATP generation from glucose is inefficient).

1. Describe Cerebral Lipid Metabolism:

   • What cannot pass BBB

   • What does the brain synthesize?

   • How do essential FAs taken up?

   • What does the brain uses Fatty acids for? Describe this thing

Describe Cerebral cholesterol metabolism

• STATs about ChL and Brain

• What cells can synthesize ChL?

• What can provide ChL?

• What does ChL synthesis Drive?

Cerebral Lipid Metabolism

• Cannot pass BBB: Nonessential fatty acids and ChL

• brain synthesizes most of its own fatty acids and cholesterol.

• Essential fatty acids (provided in diet) are taken up by specific transporters in the brain.

• Fatty acids → membrane lipids.

  • very long chain (C>22) and branched chain fatty acids in membrane lipids.

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Cerebral cholesterol metabolism

• ~20% of the body's cholesterol are in the brain.

  • ~70-80% in myelin.

• Synthesis of ChL:

  • Neurons and glial cells

• What can provide ChL:

  • Astrocytes via ApoE-cholesterol-phospholipid complexes

• What ChL synthesis drive:

  • ChL synthesis in oligodendrocytes drives myelination in early life.

Describe Niemann-Pick disease type C

• Normal Physiology?

• Pathophysiology?

• Consequence?

Niemann-Pick disease type C

• Normal:

  • Astrocytes generates ApoE-cholesterol lipoproteins

    • → Neurons Endocytosis → ChL removed in lysosomes → ER/Plasma Membrane

• Pathophysiology:

  • Defect in removal process → ChL accumulation in lysosomes.

• Consequence:

  • inhibits ganglioside degradation in neuron

  • Leads to secondary ganglioside accumulation

  • Leads to Neurodegen.

Describe Myelin Formation

• describe the myelin Sheet

• Differentaite between Oligodendrocytes/Schwann

• The myelin sheet is a multilayer cell membrane around the axon

• Oligo vs Schwann:

  • Oligodendrocytes:

    • myelinate multiple axons

    • in CNS.

  • Schwann cells:

    • myelinate only one axon

    • PNS.

Describe the composition of Brain Myelin compared to Avg. cell membrane

[REVIEW] different types of Lipids

What are the 3 structural components of glycolipids?

Glycolipids have 3 structural components

• FA chain

• Carbohydrate

• sphingosine (an amino alcohol)

1. Draw out the synthesis of glycosphingolipids

   • Where does sugar add. start/completed?

   • What form does the sugar have to be in?

   • What is the sulfate donor?

1. Sugar addition starts in the ER and completed in the Golgi.

2. Sugars have to be in a nucleotide-activated form to be added to the molecules.

3. PAPS is the sulfate donor.

1. Describe Galactocerebrosides and sulfatides

   • Function?

   • Metabolic Deficiencies →?

2. Describe Gangliosides

   • Enriched?

   • Deficiencies →?

   • Clinical Importance?

Galactocerebrosides and sulfatides

• Function:

  • main glycolipids in myelin sheet

  • Help stabilize paranodal junctions

    • (the regions adjacent to the Nodes of Ranvier)

• Metabolic deficiencies → suboptimal myelination or demyelination.

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Gangliosides

• Enriched in the neuron plasma membranes (10-12% of lipids)

• Metabolic deficiencies → neurodegeneration

  • (usually without myelination problems).

• Clinical Importance:

  • Autoantigens in certain autoimmune neuropathies.

Draw out Degradation of glycosphingolipids II and associated disease

Describe the Peroxisomes:

• Function?

• Relation to CNS?

• Defect?

Peroxisomes:

• Function:

  • Metabolizes very long chain fatty acids (VLCFAs, C>22) and branched chain fatty acids (BCFAs).

    • CNS membranes uses these

• Defect → neurological impairment.

Describe Cerebral nitrogen metabolism

• Non vs Essential AA:

• Glutamine Metabolism:

• Glutamine synthetase

• Non vs Essential AA:

  • Essential: Transported through BBB

  • Non: LImiged Transport (except arginine).

• Glutamine Metabolism:

  • Brain = net glutamine exporter

    • due to extensive glutamine synthesis by astrocytes

• Glutamine synthetase reduces the levels of toxic ammonia in the brain.

Describe the AA transporters

• L1 (Leucine-preferred) transporter

• y+ transporter:

• Na+-dependent transport

• L1 (Leucine-preferred) transporter

  • moves large neutral amino acids (LNAAs) → brain

    • (Leu, Val, Ile, His, Phe, Tyr, Trp, Met, Thr).

• y+ transporter:

  • moves cationic amino acids → brain

    • (Lys, Arg)

• Na+-dependent transport

  • Glutamine (Gln) leaves the brain ECF

Compare and Contrast BRAIN ECF vs Blood contents

Describe the relationship between L1 and maple syrup urine disease and consequences

High Blood levels of Leu → occupy L1 → other LNAA going in

• Low His, Trp and Tyr → compromise NT synthesis → severe CNS dysfunction