A study published in the May issue of Neuron indicates that the brain microglia may exert a protective role in Alzheimer´s disease (AD) by tightly wrapping around the early amyloid fibrils and plaques endorsing their compaction and insulation.
In Alzheimer´s disease two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles are the major players in neuroinflammation.
Previous research has clearly indicated pro-inflammatory activities, and increased production of major pro-inflammatory cytokines in AD. As we recently discussed, this may also include the ability of activated microglia to shift the T cells’ profile towards an inflammatory and neurotoxic IL-17+ γδ T cells phenotype.
However, it appears that a new concept is emerging where microglia, the principal brain innate neuroimmune cells, play a dichotomous role in AD. Microglia can be protective, promoting phagocytosis and clearance of Aβ. But, with disease progression, microglia become dysfunctional, release neurotoxins, lose their ability to clear Aβ and produce pro-inflammatory cytokines that promote Aβ production and accumulation.
Recently, Suzanne Hickman and Joseph El Khoury proposed that TREM2 variants contribute to AD via down regulation of the Aβ phagocytic ability.
The TREM2 gene encodes Triggering Receptor Expressed on Myeloid cells 2 protein, which is a receptor expressed on innate immune cells. Of note, the TREM2 gene is specifically expressed by microglia in the central nervous system, and recent evidence indicates that several heterozygous variants of the TREM2 gene are associated with increased susceptibility to late-onset AD with an odds ratio close to that of ApoEε4 (cf. Hickman and El Khoury, Biochem Pharmacol. 2014, 88: 495).
In the Neuron study, Peng Yuan and colleagues from the Departments of Neurology and Neuroscience, Yale University, CT, USA, demonstrate that in AD-like mice and human AD tissue the microglia processes are in close contact with individual amyloid fibrils in early non-compact filamentous plaques. The authors found that later, microglia form specialized protrusions rich in TREM2 that tightly envelop the surface of compact plaques. According to the authors, the process of tight envelopment of fibrils and early-stage plaques by the microglia processes contribute to amyloid fibril compaction.
Importantly, the authors demonstrate that in TREM2-haplodeficient mice and in humans with R47H TREM2 mutations, there was a significant reduction in amyloid plaque compaction that was associated with reduced microglia’s ability to envelop amyloid deposits.
The authors discuss that TREM2 deficiency disrupts this specialized barrier function and may thus constitute a previously unknown cellular mechanism linking TREM2 R47H variant with increased risk of dementia.
According to Dr. Jaime Grutzendler, the senior author of the Neuron study, whether a person develops symptoms may be a matter of balance, between “how many plaques you have and how contained they might be”, and that their results suggests that in AD “efforts should probably be made to enhance the immune cells’ function rather than suppress it”.
According to a Social Issues article in the Washington Post and Heather Snyder, from the Alzheimer’s Association: “There may be a window of time where this activity or behavior is positive, and there may be a window of time where this activity or behavior is negative. Timing it and being able to detect those changes is key”.
All this may indicate the complexity of the inflammatory process in Alzheimer´s disease, and opens the question or debate whether pro- or anti-inflammatory strategies should be applied in this condition.