Browsing by Subject "Amyloid‐related imaging abnormalities (ARIA)"

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    Acute communication between microglia and other immune cells in the anti‐Aβ antibody injected cortex
    (Wiley, 2025-01-03) Foley, Kate E.; Krick, Katelynn E.; Weekman, Erica M.; Wilcock, Donna M.; Neurology, School of Medicine
    Background: Anti‐Aβ immunotherapy use to treat Alzheimer’s disease is on the rise. While anti‐Aβ antibodies provide hope in targeting Aβ plaques in the brain, a major side effect of amyloid‐related imaging abnormalities (ARIA) persists with no known cause. As severe ARIA is typically seen within the first few infusions in human clinical trials, we sought to identify acute effects of anti‐Aβ antibody on brain. Method: To determine cellular changes due to anti‐Aβ antibody exposure, we intracranially injected 14mo APP male and female mice with anti‐Aβ IgG1 (6E10) or control IgG1 into the cortex. After 24hrs or 3days, we harvested the cortex and performed a glial cell enriched preparation for single cell sequencing. Cell types, proportions, and cell‐to‐cell signaling was evaluated between the two injection conditions and two acute timepoints. Result: We identified 23 unique cell clusters including microglia, astrocytes, endothelial cells, neurons, oligos/OPCs, immune cells, and unknown. The anti‐Aβ antibody injected cortices revealed more ligand‐receptor communications between cell types, as well as stronger communications at 24hrs. At 3days, while there were more L‐R communications for the anti‐Aβ antibody condition, the strength of these connections was stronger in the control IgG condition. Specific pathways such as CD48 and PD‐L1 were enriched in the anti‐Aβ antibody condition, but not the control IgG condition in microglia‐to‐microglia communication. We also found evidence of an initial and strong communication emphasis in microglia‐to‐peripheral immune cells at 24hrs, specifically in the TGFβ signaling pathway. Additionally, we found that peripheral immune cells that were exposed to anti‐Aβ antibody failed to signal via the TNF pathway, which was strongly enriched in the control IgG condition at both timepoints. Conclusion: We identify several pathways that differ between anti‐Aβ antibody and control IgG injections at acute timepoints. These data lay the groundwork for understanding the brain’s unique response to anti‐Aβ antibody and its predisposition to ARIA.
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    Understanding the cellular responses to anti‐Abeta antibodies to gain insights into mechanisms of ARIA
    (Wiley, 2025-01-03) Foley, Kate E.; Weekman, Erica M.; Wilcock, Donna M.; Neurology, School of Medicine
    Anti‐amyloid immunotherapy holds great promise for our patients and their families as the first disease‐modifying therapy for the treatment of Alzheimer’s disease (AD) to be approved. Positive clinical trials for lecanamab and donanemab showed significant and rapid lowering of brain amyloid burden and a significant slowing of cognitive decline. Amyloid‐related imaging abnormalities (ARIA) in the form of vasogenic edema (ARIA‐E) and micro ‐ and macro‐ hemorrhages (ARIA‐H) remain the major obstacle to broad use of these agents. Significant cerebrovascular pathology precludes treatment due to enhanced risk of ARIA. In addition, it is known that ApoE4 carriers are at a significantly increased risk of ARIA incidence, with 25‐40% of homozygotes developing ARIA. Understanding the mechanisms underlying ARIA is of critical importance to increase safety and broaden the use of anti‐amyloid immunotherapy. Using mouse models of amyloid deposition, we have performed systemic and intracranial anti‐beta‐amyloid antibody administration to study the potential mechanisms of both amyloid clearance and cerebrovascular disruptions that lead to ARIA. We have found that microglial activation is present along the vessels that are laden with cerebral amyloid angiopathy (CAA). Furthermore, coincident with microhemorrhage occurrence is increased expression and activity of matrix metalloproteinases (MMPs) MMP9 and MMP3. MMPs are known to degrade basement membranes and tight junction proteins that could lead to disruption of the blood‐brain barrier and, ultimately, edema and hemorrhage. in fact, it has long been understood that MMP9 plays a critical role in the hemorrhagic transformation of ischemic stroke. We have performed single‐cell transcriptomic analysis to examine the glial responses following a single anti‐amyloid immunotherapy and we find significant microglial population shifts and also enhanced signaling from microglia to perivascular macrophages, potentially implicating these cells as a key player in the development of ARIA. Ultimately, discovering the mechanisms of ARIA will result in the development of safer, next‐generation antibody therapy that has reduced ARIA risk, and also could lead to the identification of adjunct treatments that can be co‐administered with the anti‐amyloid immunotherapy to prevent the occurrence of ARIA in those at risk.