Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer’s disease mouse model

Mar 21, 2025Journal of neuroinflammation

Reducing Asrij/OCIAD1 lowers inflammation in brain immune cells and improves amyloid beta buildup in an Alzheimer's mouse model

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

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.

AI 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.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (PDF) ↗View full text (HTML) ↗

Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer’s disease mouse model

Abstract

Key numbers

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Key numbers

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief