Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques

By Carlo Condello, Peng Yuan, Aaron J. Schain, J. Grutzendler. Nature Communications, 2015

607 citations recorded by the source corpus.

In Alzheimer’s disease (AD), β-amyloid (Aβ) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown. Here we show that microglia constitute a barrier with profound impact on plaque composition and toxicity. Using high-resolution confocal and in vivo two-photon imaging in AD mouse models, we demonstrate that this barrier prevents outward plaque expansion and leads to compact plaque microregions with low Aβ42 affinity. Areas uncovered by microglia are less compact but have high Aβ42 affinity, leading to the formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In ageing, microglia coverage is reduced leading to enlarged protofibrillar Aβ42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-Aβ immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar Aβ hotspots may constitute novel therapeutic and clinical imaging targets for AD. In Alzheimer’s disease (AD), β-amyloid plaques are tightly enveloped by microglia but the significance of this phenomenon is unknown. Here the authors used confocal and in vivotwo-photon imaging in AD mouse models and revealed that microglia constitute a barrier that seems to prevent the formation of neurotoxic hotspots of protofibrillar β-amyloid.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/ab2d9f956c1e88cb5f65053d2c413c8dfbd4b415

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

1. D. Holtzman
2. M. Colonna
3. Hui Wang
4. Shenrui Guo
5. Yafu Yin

In Physiology

1. D. Holtzman
2. M. Colonna
3. John R. Cirrito
4. J. Long
5. D. Selkoe
6. Berislav Zlokovic

Citations in the corpus

• Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, background): “Furthermore, a recent study showed that microglia tightly surround plaques and prevent further growth (Condello et al., 2015).”
• TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques (2016, background): “Recently, microglia around Aβ plaques were shown to form a physical barrier that prevents outward plaque expansion and leads to compact plaque microregions with low Aβ1-42 affinity (Condello et al., 2015).”
• Microglia Polarization From M1 to M2 in Neurodegenerative Diseases (2022, background): “Bone marrow mesenchymal stem cell (BMSC)-derived exosome significantly reduces inflammation and demyelination in the CNS, attenuates clinical manifestation of EAE, and significantly increases M2 markers and decreases M1 markers (Li et al., 2019).”
• Microglia in Alzheimer’s disease (2018, background): “Relative to the most common apoE3 variant, a single apoE4 or apoE2 allele confers an approximately threefold increased or approximately twofold reduced risk of developing AD, respectively (Corder et al., 1993, 1994; Strittmatter et al., 1993; Farrer et al., 1997).”