Deterioration of neuroimmune homeostasis in Alzheimer's Disease patients who survive a COVID-19 infection

• Published in: Journal of neuroinflammation Vol. 21; no. 1; pp. 202 - 27
• Main Authors: Villareal, Jonathan A B, Bathe, Tim, Hery, Gabriela P, Phillips, Jennifer L, Tsering, Wangchen, Prokop, Stefan
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17.08.2024; BMC
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - immunology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Astrocytes; Astrocytes - immunology; Astrocytes - metabolism; Astrocytes - pathology; Brain - immunology; Brain - metabolism; Brain - pathology; COVID-19; COVID-19 - complications; COVID-19 - immunology; COVID-19 - pathology; Female; Health aspects; Homeostasis - physiology; Humans; Male; Medical research; Medicine, Experimental; Microglia; Microglia - immunology; Microglia - metabolism; Microglia - pathology; Middle Aged; Neuroimmunology; Neuroimmunomodulation - physiology; Neuroinflammation; Physiological aspects; SARS-CoV-2; Systemic infection; United States; COVID-19; Alzheimer’s disease; Astrocytes; Oligodendrocytes; Neuroinflammation; Systemic infection; Microglia
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-024-03196-3

Growing evidence has implicated systemic infection as a significant risk factor for the development and advancement of Alzheimer's disease (AD). With the emergence of SARS-CoV-2 (COVID-19) and the resultant pandemic, many individuals from the same aging population vulnerable to AD suffered a severe systemic infection with potentially unidentified long-term consequences for survivors. To study the impact of COVID-19 survival on the brain's intrinsic immune system in a population also suffering from AD, we profiled post-mortem brain tissue from patients in the UF Neuromedicine Human Brain and Tissue Bank with a diagnosis of AD who survived a COVID-19 infection (COVID-AD) and contrasted our findings with AD patients who did not experience a COVID-19 infection, including a group of brain donors who passed away before arrival of SARS-CoV-2 in the United States. We assessed disease-relevant protein pathology and microglial and astrocytic markers by quantitative immunohistochemistry and supplemented these data with whole tissue gene expression analysis performed on the NanoString nCounter platform. COVID-AD patients showed slightly elevated Aβ burden in the entorhinal, fusiform, and inferior temporal cortices compared to non-COVID-AD patients, while tau pathology burden did not differ between groups. Analysis of microglia revealed a significant loss of microglial homeostasis as well as exacerbated microgliosis in COVID-AD patients compared to non-COVID-AD patients in a brain region-dependent manner. Furthermore, COVID-AD patients showed reduced cortical astrocyte numbers, independent of functional subtype. Transcriptomic analysis supported these histological findings and, in addition, identified a dysregulation of oligodendrocyte and myelination pathways in the hippocampus of COVID-AD patients. In summary, our data demonstrate a profound impact of COVID-19 infection on neuroimmune and glial pathways in AD patients persisting for months post-infection, highlighting the importance of peripheral to central neuroimmune crosstalk in neurodegenerative diseases.