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AAIC 2023 | Blood proteins link cerebrovascular damage with immune-mediated neurodegeneration

Katerina Akassoglou, PhD, University of California San Francisco, San Francisco, CA, shares novel findings on the role of blood proteins in the induction of pathogenic neuroinflammation in neurologic diseases. Given the long-known involvement of cerebrovascular dysfunction in Alzheimer’s disease, Dr Akassoglou and her team wanted to better understand the mechanisms that link blood-brain barrier disruption to neurodegeneration. Functional multiomics studies showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages. In particular, fibrinogen was shown to be necessary and sufficient for the induction of pathogenic neuroinflammation, activating neurodegenerative signature expression in microglia. In mouse models, fibrinogen was shown to cause spine elimination and promote cognitive dysfunction via its action on microglia. In this way, the study demonstrates how blood-brain-barrier dysfunction, and resultant exposure to blood leaking into the brain, leads to neurotoxic immune responses and neurodegeneration. This interview took place at the Alzheimer’s Association International Conference® (AAIC) 2023 in Amsterdam, Netherlands.

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Transcript (edited for clarity)

Cerebrovascular changes in Alzheimer’s disease are very early events that correlate with early onset but also worse prognosis in Alzheimer’s disease patients. There has always been this chicken and egg question whether there secondary to disease pathogenesis or drivers of disease and in my talk today at the AAIC meeting, I presented a key culprit in the blood, the blood protein fibrinogen that is a driver of neurotoxic immune responses in the brain in Alzheimer’s disease and methods to be able to target this pathway in Alzheimer’s disease and neurodegeneration...

Cerebrovascular changes in Alzheimer’s disease are very early events that correlate with early onset but also worse prognosis in Alzheimer’s disease patients. There has always been this chicken and egg question whether there secondary to disease pathogenesis or drivers of disease and in my talk today at the AAIC meeting, I presented a key culprit in the blood, the blood protein fibrinogen that is a driver of neurotoxic immune responses in the brain in Alzheimer’s disease and methods to be able to target this pathway in Alzheimer’s disease and neurodegeneration.

One of the technologies that we employed in the lab to be able to dissect the molecular and cellular interface that the blood proteins utilize to interact with nervous system cells is multiomic profiling, where we integrate transcriptomic with global phosphoproteomic approaches together with genetic loss of function studies to ask the question, what are the key blood proteins that activate pathogenic pathways in innate immune cells? And is there any selectivity among blood proteins to mediate these effects? What we found is that actually blood proteins are not interchangeable, but they have distinct receptor mediated pathways in immune cells with fibrin being a key driver that is necessary and sufficient to induce neurotoxic pathways in innate immunity with detrimental effects in cognitive impairment in Alzheimer’s disease models. These studies really changed the way we think about the blood-brain barrier as downstream of inflammation to actually be an apical driver that polarizes innate immunity towards these toxic phenotypes.

The results from our study in regard to how does the blood polarize microglia cells led us to the development of what we call the blood microglia network, which is a series of genes that participate in neurodegeneration, oxidative stress, glutathione metabolism and other inflammatory processes, all of which lead to microglial neurotoxicity towards synaptic dysfunction, as well as also myelin loss in the brain. This shows that blood, the blood in the brain can be an upstream driver of these neurotoxic responses in Alzheimer’s disease, but also other neurodegenerative conditions that have blood in the brain, which could be diseases of autoimmune origin like multiple sclerosis or traumatic injuries or also other neuropathologies.

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Disclosures

K.A. is the scientific founder, advisor and shareholder of Therini Bio, Inc. Her interests are managed by Gladstone Institutes according to its conflict of interest policy.