Short Article on Alzheimer’s Disease: #3 Microglia

One of the pathological hallmarks of Alzheimer’s disease is the accumulation of amyloid beta in senile plaques. This is due to an imbalance between an increased production of amyloid beta and its clearance mechanisms or its clearance mechanisms being impaired. Amyloid beta peptides have high affinity for many receptors and their clearance can occur in cells via several processes. For instance, the transcytosis of monomeric amyloid beta across the brain blood barrier can be achieved via the low-density lipoprotein receptor-related protein 1 (LRP1) as seen in a previous blog post. Another process is the internalisation of amyloid beta by the brain macrophages or microglia. Although their role is beneficial in clearing amyloid beta, constant microglia activation might further contribute to neuroinflammation.

Microglia as first line of defence in the brain
Microglia are immune cells, resident in the central nervous system (CNS) that derive from yolk sac progenitors during embryogenesis. They play a key role in brain maintenance and have recently been shown to mediate synaptic plasticity, learning and memory.[1] In their “resting” form, microglia constantly scan the environment by stretching out their long processes in order to detect immune threats while maintaining homeostasis in the CNS.[2] They are extremely plastic and are able to respond quickly to changes in their extracellular environment caused for instance by stress, trauma, diseases or upon activation by various factors such as pro-inflammatory cytokines, cell necrosis factors, lipopolysaccharide or a variation in the extracellular potassium levels.[2] These factors induce a change in their morphology and microglia will shift from a ramified to an amoeboid form that will allow their phagocytosis activity.[2,3] Iba1, a protein expressed in microglia and upregulated upon their activation, represents a useful marker for researchers to visualise these cells.

Microglia and Alzheimer's
With regard to Alzheimer’s disease, microglia have a dual role. On a positive side, they have a neuroprotective effect and will clear amyloid beta/senile plaques through phagocytosis. As a reminder, amyloid beta peptides are formed by the proteolytic cleavage of the transmembrane protein APP. Although they are first produced as monomers, they will clump together to form aggregates and senile plaques, with the smallest aggregates thought to be the most neurotoxic.

On the other hand, continuous activation of microglia also contributes to neuroinflammation by releasing pro-inflammatory cytokines. In particular, microglia are a well-known source of reactive oxygen species (ROS) in the brain and will as a result promote neuronal loss mediated by oxidative stress. Indeed, ROS are extremely reactive species and if not scavenged by antioxidants, they will damage DNA and membrane lipids to form more stable molecules such as 8-OHdG and 4-HNE, which can be useful markers in AD research.[3]

 

Newmarket Scientific, a distributor of life science reagents in the UK and Ireland with a strong focus in neuroscience research, provides products from a number of different suppliers and in particular, Biosensis and StressMarq, who provide several antibodies and ELISA kits (8-OHdG) for Alzheimer’s, oxidative stress and lipid peroxidation research.

Further reading
- Oxidative Damage – The Damaging Effect of Reactive Oxygen Species ROS
- Amyloid Beta Plaque Staining
- Short Articles on Alzheimer’s Disease:
#1 Amyloid beta Formation
#2 Amyloid beta accumulation: imbalance of the production and clearance of Abeta
#4 Tau Phosphorylation
#5 Tau Aggregation and Propagation

References
[1] Microglia across the lifespan: from origin to function in brain development, plasticity and cognition, Tay TL et al, J Physiol. 2017 Mar 15; 595(6): 1929–1945.
[2] Microglia, Wikipedia https://en.wikipedia.org/wiki/Microglia accessed 27/07/2018
[3] Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress, Bisht K. et al, Neurobiol Stress. 2018 Nov; 9: 9–21.

Written by Magalie Dale
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