1.2 Microglia and Oligodendrocytes

Two (broad) categories of cells in the nervous system

• Neurons

• Glia

Role of Neurons

Main signalling cells;

Receive, process and transmit information

Glia Types

• Astrocytes

• Oligodendrocytes

• Microglia

Origin of Neurons, Astrocytes and Oligodendrocytes

A neural stem cell

Origin of Microglia

Macrophage lineage (immune/macrophage lineage, not neural); they enter the brain before birth. So they are NOT neural cells

Microglia

The brain's resident immune surveillance and clean-up cells

Key characteristics of Microglia

• Highly branched (ramified)

• Distributed throughout the CNS in a regular pattern

• Phagocytic immune cells

• About 5% of brain cells

• Can be good (protective) or bad (damaging)

How do microglia behave in the (healthy) CNS?

They continuously sample and monitor the environment for damage or abnormality and respond rapidly when something goes wrong

What triggers microglial activation?

• Injury

• Inflammation

• Immune insults

Effects of microglial activation

• Increased macrophage/immune functions

• Increased Phagocytosis

How is microglial activation a graded spectrum?

It has multiple intermediate states & is context dependent, regulated by the balance of OFF and ON signals

Examples of microglial ON & OFF signals

ON: ATP, Toll-like receptors (TLR2/4), TNF and CSF1

OFF: TGF-β, fractalkine (CX3CL1) and BDNF

Function of OFF signals

Help maintain microglia in a less activated state

Activated microglia can present antigen to what cells?

T cells/lymphocytes - which combat pathogens

Signalling molecules released by microglial activation

• TNF

• IL-1β

• Reactive oxygen species (ROS)

• Nitric oxide (NO)

Pro-inflammatory factors released by microglia

• TNFα

• IL-1β

• IL-6

• ROS

• NO

associated particularly with acute injury and can contribute to tissue damage.

Anti-inflammatory/Repair-associated factors released by microglia

• IL-10

• TGF-β

• IGF-1

associated with tissue repair

Protective roles of microglia

• Remove damaged material

• Phagocytose degenerating tissue

• Release repair-promoting factors and support remyelination

Damaging roles of Microglia

• Releases pro-inflammatory molecules & Contributes to inflammation

• Damage oligodendrocytes and myelin

Neuropathologies in which Microglia are relevant

Most, particularly:

• MS

• Alzheimer's disease

• Brain injury and stroke

Multiple Sclerosis (MS)

An autoimmune, CNS demyelinating disease wherein immune cells attack the body's own myelin.

Damaging role of Microglia in MS

Release pro-inflammatory molecules (e.g. TNFα, NO) that damage oligodendrocytes and myelin

Beneficial role of Microglia in MS

Phagocytose degenerating myelin, release repair factors (e.g. FGF-2) and support remyelination

White matter

Contains bundles of myelinated axons connecting brain regions

Why is White matter essential?

Rapid communication, integration of information between brain regions and supporting the brain's enormous computational capacity

Oligodendrocytes

Produce and maintain myelin around CNS axons

Function of myelin

Forms an insulating layer around axons, allowing action potentials to travel rapidly.

Allows for:

• Rapid axonal conduction

• Efficient communication between brain regions

• Axonal integrity and survival

Relationship between Oligodendrocytes and Axons

They form functional units; the health and function of each are closely linked.

Consequences of myelin loss

Conduction block → axonal dysfunction → axonal degeneration

Proteins whose absence causes axonal degeneration

• PLP

• CNP

• GalC

Is myelination finished once the brain has developed?

No; new Oligodendrocytes can be generated throughout life

Adaptive myelination

Learning stimulates Oligodendrocyte Progenitor Cells (OPCs) to generate new Oligodendrocyte, which myelinate the new connections formed.

Experimental evidence for Adaptive myelination

Mice learning to cope with uneven wheel rung spacing; blocking myelination reduced their ability to learn the task quickly

Why does life-long Oligodendrocyte generation matter?

Contributes to:

• Learning

• Brain plasticity

• Maintaining cognitive function

• Myelinating new connections

• Repairing damaged myelin

Factors that regulate myelination

• Growth factors

• Axonal factors

• Neurotransmitters

Effect of learning a new skill on white matter

Associated with an increase in white matter, showing experience can alter white matter organisation

White matter and Ageing

White matter shrinks after approximately age 50 in humans, associated with cognitive decline

Possible contributors to age-related white matter shrinkage

• Reduced replacement of myelin lost to wear and tear

• Reduced myelination of new connections

• Reduced capacity for growth, learning and plasticity

How does Age-related decline in myelin repair relate to neuropathology?

Relevant to diseases such as MS and Alzheimer's:

Ageing leads to reduced myelin repair and poorer maintenance of white matter

Therapeutic aims targeting oligodendrocytes and myelin

• Promote oligodendrocytes generation

• Promote remyelination

• Improve repair following CNS damage

What drug is used for remyelination?

Metformin

Overall relationship between microglia and myelin health

Microglia can have opposing effects:

• Pro-inflammatory activity damages oligodendrocytes and myelin (demyelination)

• Phagocytosis and repair promote remyelination