The effect of Abi3 locus deletion on the progression of Alzheimer's disease-related pathologies.

Human 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 (Aß) 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 Aß-amyloidosis mouse model and aged them until 4.5-month-old. Here, we demonstrate that deletion of the Abi3 locus increased Aß 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 Aß accumulation and inflammation starting from earlier stages of the pathology.

Network analysis reveals strain-dependent response to misfolded tau aggregates.

Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimer's disease. However, it is unknown what mechanisms underly these effects of genetic background on modeling Alzheimer's disease, specifically tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT (P301L). To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of 6-month-old C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n=64). We also measured tau seeding activity in the cortex of these mice. We identified three gene signatures: core transcriptional signature, unique signature for each wild-derived genetic background, and tau seeding-associated signature. Our data suggest that microglial response to tau seeds is elevated in CAST/EiJ and PWK/PhJ mice. Together, our study provides the first evidence that mouse genetic context influences the seeding of tau. SUMMARY: Seeding of tau predates the phosphorylation and spreading of tau aggregates. Acri and colleagues report transcriptomic responses to tau and elevated tau seeds in wild-derived mice. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.

Network analysis identifies strain-dependent response to tau and tau seeding-associated genes.

Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT. To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n = 64) and determined core transcriptional signature conserved in all genetic backgrounds and signature unique to wild-derived backgrounds. By measuring tau seeding activity using the cortex, we identified 19 key genes associated with tau seeding and amyloid response. Interestingly, microglial pathways were strongly associated with tau seeding activity in CAST/EiJ and PWK/PhJ backgrounds. Collectively, our study demonstrates that mouse genetic context affects tau-mediated alteration of transcriptome and tau seeding. The gene modules associated with tau seeding provide an important resource to better model tauopathy.

Deletion of the Alzheimer's disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice.

Alzheimer's disease (AD) genetics studies have identified a coding variant within ABI3 gene that increases the risk of developing AD. Recently, we demonstrated that deletion of the Abi3 gene locus dramatically exacerbates AD neuropathology in a transgenic mouse model of amyloidosis. In the course of this AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice. Here, we report our investigation into this serendipitous metabolic finding. Specifically, we demonstrate that mice with deletion of the Abi3 gene locus (Abi3-/- ) have dramatically increased body weight and body fat. Further, we determined that Abi3-/- mice have impaired energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of Abi3-/- mice. Altogether, this investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight. While our previous findings indicated the importance of Abi3 in neurodegeneration, this study indicates that Abi3 related functions are also essential for metabolic regulation.

Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aß amyloidosis.

Recently, 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 ß (Aß) 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 Aß accumulation and neuroinflammation.