Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration, 2019, Joshi et al

Andy · Oct 15, 2019

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration—one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.
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Paywall, https://www.nature.com/articles/s41593-019-0486-0
Scihub, https://sci-hub.se/10.1038/s41593-019-0486-0

Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, or Lou Gehrig’s disease, share a common mode of damaging brain cells, the scientists learned in studying both human cells in culture and mouse models of the diseases. This damage can be blocked by administering a substance that inhibits a critical step in that process.

The new study implicates two types of normally protective brain cells called glial cells in tripping off neuronal destruction: Microglia monitor the brain for potential trouble — say, signs of tissue injury or the presence of invading microbial pathogens — and scavenge debris left behind by dying cells or protein aggregates. Astrocytes, which outnumber the brain’s neurons nearly 5 to 1, release growth factors, provide essential metabolites and determine the number and placement of the connections neurons make with one another.

Neuronal bits and fragments are perceived as foreign and targeted for clearance by microglia. But a vicious cycle of glial-cell activation and inflammation can occur in the absence of neuronal debris.

Mochly-Rosen, the George D. Smith Professor in Translational Medicine, and her colleagues discovered that mitochondria, essential components of cells, were conveying deleterious signals from microglia to astrocytes and from astrocytes to neurons. Mitochondria are tiny power packs: They furnish cells with energy. A typical nerve cell contains thousands of them. Their ability to communicate death signals from one cell to another was unexpected.
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http://med.stanford.edu/news/all-ne...ed-in-several-neurodegenerative-diseases.html

janice · Oct 15, 2019

This I feel is very interesting and is quite a hot topic in a fair few areas I understand.
I did a pilot study looking at Beta-herpes viral load on the Stanley Neuropathology consortium collection of cerebellums from 15 normals, 15 MMD and 15 schizophrenia about 10 years ago.( Unfortunately I crashed out the M.Sc. course cos of ME so didn’t get to replicate or publish)
Anyway I found out that HHV6A gave a strong signal in some of the brains in all three groups. Probably in Purkinje cells.

mariovitali · Oct 15, 2019

@Andy this is very interesting.

cc @Perrier

Inhibition of Drp1 provides neuroprotection in vitro and in vivo
J Grohm,1 S-W Kim,2,3 U Mamrak,2,3 S Tobaben,1 A Cassidy-Stone,4 J Nunnari,4 N Plesnila,2,3 and C Culmsee1,*
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Abstract
Impaired regulation of mitochondrial dynamics, which shifts the balance towards fission, is associated with neuronal death in age-related neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. A role for mitochondrial dynamics in acute brain injury, however, has not been elucidated to date. Here, we investigated the role of dynamin-related protein 1 (Drp1), one of the key regulators of mitochondrial fission, in neuronal cell death induced by glutamate toxicity or oxygen–glucose deprivation (OGD) in vitro, and after ischemic brain damage in vivo. Drp1 siRNA and small molecule inhibitors of Drp1 prevented mitochondrial fission, loss of mitochondrial membrane potential (MMP), and cell death induced by glutamate or tBid overexpression in immortalized hippocampal HT-22 neuronal cells. Further, Drp1 inhibitors protected primary neurons against glutamate excitotoxicity and OGD, and reduced the infarct volume in a mouse model of transient focal ischemia. Our data indicate that Drp1 translocation and associated mitochondrial fission are key features preceding the loss of MMP and neuronal cell death. Thus, inhibition of Drp1 is proposed as an efficient strategy of neuroprotection against glutamate toxicity and OGD in vitro and ischemic brain damage in vivo
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...Glutamate, again?

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Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration, 2019, Joshi et al

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Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration, 2019, Joshi et al

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