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Microglia contribute to the spread of Alzheimer-typical changes in the brain

Alzheimer's disease is neuropathologically characterised by deposits of extracellular amyloid, known as Aβ. The brain's microglia, as part of our innate immune system, reacts to these proteins by enveloping Aβ plaques and forming a barrier around them. Soluble precursors, so-called Aβ-oligomers, bind to microglial receptors (TLR, RAGE and TREM2) and are taken up by the cells (phagocytosed, see following figure). This reduces neuronal damage. Mutations in the TREM2 gene increase the risk of developing Alzheimer's disease. Most authors therefore assume a neuroprotective function of microglia.

Fig. In Alzheimer's disease, microglia and astrocytes are activated by Aβ (shown here by pink dots that aggregate to form Aβ plaques). Both cell types then begin to divide and transform into a 'reactive' glial cell. Activated microglia envelop Aβ-plaques, preventing them from spreading. This activation occurs via an interleukin released by astrocytes, IL-3. Aβ-plaques are furthermore cleared through the perivascular (glymphatic) space (indicated by the dashed arrows). Aβ-aggregates reduce blood flow (via an effect on pericytes) and disrupt neuronal and especially synaptic functions in addition to damaging the blood-brain barrier (modified Fig. 2.4 from Klimaschewski L.P. Parkinson's and Alzheimer's Today - About Neurodegeneration and its Therapy. Springer, 2022).

However, microglia may also be excessively activated, which can be observed in advanced stages of the disease, particularly in regions of high pTau concentrations. Numerous pro-inflammatory cytokines and migrated T lymphocytes are found there. This is a 'sterile' inflammatory reaction (i.e. germs play no role). It leads to an accelerated loss of synapses and the death of nerve cells following activation of the complement system. Microglial cells produce more of the C1 complex, which binds to synaptic membranes and leads to the activation of the classic complement cascade and subsequent phagocytosis of synapses.

Recently, d'Errico and colleagues have uncovered another disease-promoting aspect of microglia in Nature Neuroscience. Namely, the cells contribute decisively to the proliferation of amyloid plaques. The transcription factor IRF8 is required for this. After transplanting embryonic neurons into the brain of a mouse that forms Aβ-plaques, the authors of the paper discovered a strong connection between the migration of activated microglia and the formation of new Aβ-plaques in grafts of intact neuronal cells. This effect did not occur when the microglia had already aged or lacked the transcription factor IRF8, which seems to be responsible for microglial migration.

Other studies support a disease-promoting role for microglia, as their reduction after administration of an inhibitor of the CSF1 receptor (PLX5622) in a mouse model of Alzheimer's disease leads to reduced Aβ aggregation (CSF1 is a macrophage/microglia stimulating factor). Further studies have shown that activation of microglia could be a cause of pathological tau spreading in the cerebral cortex. It can further be assumed that microglial cells are directly involved in the phagocytosis of tau deposits, the so-called tangles.

Taken together, the new results underline the Janus-faced nature of microglia. On the one hand, the cells inhibit the spread of Aβ plaques by surrounding and phagocytosing existing Aβ accumulations. On the other hand, microglia facilitate the formation of new Aβ-plaques by transporting phagocytosed Aβ-peptides and releasing them elsewhere.


Chen Y, Colonna M (2022) Two-faced behavior of microglia in Alzheimer’s disease. Nature Neuroscience 25:3

d’Errico P, Ziegler-Waldkirch S, Aires V, ... , Prinz M, Meyer-Luehmann M (2022) Microglia contribute to the propagation of Aβ into unaffected brain tissue. Nature Neuroscience 25:20

Image credit: iStock/selvanegra


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