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Browsing by Author "Al-Amin, Md Mamun"
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Item Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis(American Association for the Advancement of Science, 2021-11) Karahan, Hande; Smith, Daniel C.; Kim, Byungwook; Dabin, Luke C.; Al-Amin, Md Mamun; Wijeratne, H.R. Sagara; Pennington, Taylor; di Prisco, Gonzalo Viana; McCord, Brianne; Lin, Peter Bor-Chian; Li, Yuxin; Peng, Junmin; Oblak, Adrian L.; Chu, Shaoyou; Atwood, Brady K.; Kim, Jungsu; Medical and Molecular Genetics, School of MedicineRecently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid β (Aβ) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knockout (“Abi3−/−”) mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aβ accumulation and neuroinflammation.Item The effect of Abi3 locus deletion on the progression of Alzheimer's disease-related pathologies(Frontiers Media, 2023-02-21) Karahan, Hande; Smith, Daniel C.; Kim, Byungwook; McCord, Brianne; Mantor, Jordan; John, Sutha K.; Al-Amin, Md Mamun; Dabin, Luke C.; Kim, Jungsu; Medical and Molecular Genetics, School of MedicineHuman genetics studies of Alzheimer’s disease (AD) have identified the ABI3 gene as a candidate risk gene for AD. Because ABI3 is highly expressed in microglia, the brain’s immune cells, it was suggested that ABI3 might impact AD pathogenesis by regulating the immune response. Recent studies suggest that microglia have multifaceted roles in AD. Their immune response and phagocytosis functions can have beneficial effects in the early stages of AD by clearing up amyloid-beta (Aβ) plaques. However, they can be harmful at later stages due to their continuous inflammatory response. Therefore, it is important to understand the role of genes in microglia functions and their impact on AD pathologies along the progression of the disease. To determine the role of ABI3 at the early stage of amyloid pathology, we crossed Abi3 knock-out mice with the 5XFAD Aβ-amyloidosis mouse model and aged them until 4.5-month-old. Here, we demonstrate that deletion of the Abi3 locus increased Aβ plaque deposition, while there was no significant change in microgliosis and astrogliosis. Transcriptomic analysis indicates alterations in the expression of immune genes, such as Tyrobp, Fcer1g, and C1qa. In addition to the transcriptomic changes, we found elevated cytokine protein levels in Abi3 knock-out mouse brains, strengthening the role of ABI3 in neuroinflammation. These findings suggest that loss of ABI3 function may exacerbate AD progression by increasing Aβ accumulation and inflammation starting from earlier stages of the pathology.