Asrij depletion ameliorates cognitive impairments and reduces Aβ deposition in an Alzheimer's mouse model.
Depletion of Asrij leads to decreased neuronal and synaptic damage in the APP/PS1 mouse model of Alzheimer's disease.
Microglia lacking Asrij show reduced proliferation and decreased activation related to Aβ plaques.
Transcriptomic analysis indicates that Asrij depletion upregulates energy metabolism pathways in microglia.
A decrease in pro-inflammatory cytokines and reduced activation of signaling pathways (STAT3 and NF-κB) is observed following Asrij depletion.
Overall, increased levels of Asrij may promote inflammatory microglial activation, contributing to the progression of Alzheimer's disease.
Simplified
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Aβ pathology in vivo is unclear.
METHODS: To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We used the Morris water maze and open field test to assess behavioral performance. Using immunohistochemistry and biochemical analyses, we evaluated load, neuronal and synaptic damage, and gliosis. Further, we utilized confocal microscopy imaging, flow cytometry, and RNA sequencing analysis to comprehensively investigate changes in microglial responses to Aβ pathology upon Asrij depletion.
RESULTS: Asrij depletion ameliorates cognitive impairments, Aβ deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activation. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and impedes the acquisition of a pro-inflammatory disease-associated microglia (DAM) state. Reduced levels of proinflammatory cytokines and decreased STAT3 and NF-κB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology.
CONCLUSIONS: In summary, we show that Asrij depletion ameliorates Aβ pathology, neuronal and synaptic damage, gliosis, and improves behavioral performance in APP/PS1 mice. This supports that Asrij exacerbates the AD pathology. Mechanistically, Asrij is critical for the development of DAM and promotes neuroinflammatory signaling activation in microglia, thus restricting neuroprotective microglial responses. Hence, reducing Asrij in this context may help retard AD. Our work positions Asrij as a critical molecular regulator that links microglial dysfunction to AD pathogenesis.
Key numbers
10 of 13
Improvement in cognitive performance
AD/KO mice showed improved latency in the Morris water maze test compared to AD mice.
6 of 6
Reduction in deposition
AD/KO mice exhibited significantly lower levels in the cortex and hippocampus compared to AD mice.
3-fold
Decrease in microglial activation
Asrij-deficient microglia showed a 3-fold reduction in the volume of Aβ plaques internalized.
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Declarations. Ethics approval and consent to participate: All mice experiments were approved by the JNCASR institutional animal ethics committee (project #MSI012) and were conducted in accordance with the standard guidelines. This work did not involve the use of material from human subjects. Consent for publication: All authors have read and approved the final manuscript for publication. Competing interests: The authors declare no competing interests.
