Lecture 10 - The role of Glial Cells in the Brain II

What are microglia and what percentage of glial cells do they make up?

Microglia are the resident immune cells of the CNS and make up 5–20% of glial cells, depending on brain region

What is the embryonic origin of microglia, and how is it different from other glia?

Microglia originate from yolk sac macrophages (myeloid lineage) that migrate into the brain around E8–E9 (mice). Unlike astrocytes and oligodendrocytes (neuroectoderm-derived), they do not arise from the neural tube

How do microglia maintain their population in the CNS?

Microglia maintain themselves via self-renewal and local proliferation rather than replacement from bone marrow

What is the general lifespan and turnover rate of microglia in humans?

Microglia are long-lived cells, with some surviving over 20 years, and show ~30% turnover per year under normal conditions

What are the three main morphological forms of microglia?

• Ramified (resting): long branched processes, constant surveillance.

• Bushy: early activation, often linked to neurodegeneration.

• Amoeboid (activated): rounded, motile, phagocytic during injury/infectio

What are some ultrastructural features of microglia?

Microglia show peripheral heterochromatin, rough ER cisternae, and Golgi complexes, supporting cytokine synthesis and secretion

What homeostatic roles do microglia play in brain development and health?

Roles include:

• Synaptic pruning via complement receptors (C1q, C3).

• Phagocytosis of apoptotic neurons.

• Activity-dependent synapse elimination.

• Support of neurogenesis (especially in hippocampus).

• Trophic factor release to support neuronal health.

What study linked microglial pruning to autism spectrum disorder?

Paolicelli et al., 2011 showed that impaired microglial pruning can lead to abnormal neural connectivity, linked to ASD

What immune functions do microglia perform?

They act as CNS immune cells by:

• Phagocytosing debris, pathogens, and apoptotic cells.

• Presenting antigens via MHC molecules.

• Releasing cytokines and chemokines.

• Monitoring the environment with pattern recognition receptors (PRRs).

What are PAMPs and DAMPs, and give examples of each.

• PAMPs (Pathogen-Associated Molecular Patterns): microbial signals (e.g., LPS, viral RNA).

• DAMPs (Damage-Associated Molecular Patterns): host-derived stress signals (e.g., ATP, α-synuclein, mitochondrial DNA)

What receptors do microglia use to detect PAMPs and DAMPs?

Microglia detect them with pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs)

What are the two main functional states of microglia?

• Resting (ramified): synaptic pruning, neurogenesis, surveillance.

• Activated (amoeboid): motile, phagocytic, cytokine release, protective or damaging depending on phenotype

What activates the M1 microglial phenotype, and what do they release?

M1 microglia are activated by LPS or IFN-γ. They release TNF-α, IL-6, IL-1β, nitric oxide, and reactive oxygen species

What is the functional outcome of M1 microglial activation?

M1 microglia promote neurotoxicity, synaptic dysfunction, and cell death, especially in chronic neurodegeneration

What activates the M2 microglial phenotype, and what do they release?

M2 microglia are activated by IL-4 or IL-13. They release IL-10, TGF-β, and trophic factors

What is the functional outcome of M2 microglial activation?

M2 microglia promote repair, tissue remodeling, and neuronal survival, acting in a neuroprotective role

M2 microglia promote repair, tissue remodeling, and neuronal survival, acting in a neuroprotective role

No. Microglia exist on a continuum of activation states and can switch between M1- and M2-like functions depending on the local environment

How do microglia respond in Alzheimer’s disease?

They cluster around amyloid-β plaques. Initially they phagocytose Aβ, but chronic activation leads to excessive cytokine release and oxidative stress, worsening neurodegeneration

How do microglia contribute to Parkinson’s disease?

Microglia are activated by α-synuclein aggregates, releasing cytokines and reactive species that contribute to dopaminergic neuron loss in the substantia nigra

What role do microglia play in multiple sclerosis (MS)?

In MS, microglia present antigens and release inflammatory mediators, contributing to demyelination and neuronal damage

What is the link between microglia and autism spectrum disorders (ASD)?

Abnormal microglial synaptic pruning results in excessive or miswired neural connections, associated with ASD pathophysiology

How do microglia respond to traumatic brain injury (TBI) and stroke?

They become rapidly activated, producing cytokines that can cause secondary injury, but also clear debris and support repair in later stages

Why is chronic overactivation of microglia harmful?

Persistent activation causes release of superoxide, nitric oxide, and TNF-α, creating a neurotoxic environment that accelerates neurodegeneration

What external factors can trigger microglial overactivation?

Environmental toxins such as pesticides and air pollutants can drive chronic microglial activation, contributing to brain injury and disease

What are common markers used to identify microglia experimentally?

• IBA1: general microglial marker.

• CD68: marker of activated microglia.

• DAPI: nuclear stain (not specific to microglia)