Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer’s disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants—WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick’s disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.

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Background The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer’s disease (AD), but little is known about its function in relation to AD pathogenesis. Methods Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD—amyloid β plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies. Results Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3−/− mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2−/− mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aβ deposition. Additionally, in Abi3-Gngt2−/− mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. Conclusions These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.

Aims To illuminate the pathological synergy between Aβ and tau leading to emergence of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), here, we have performed a comparative neuropathological study utilising three distinctive variants of human tau (WT tau, P301L mutant tau and S320F mutant tau). Previously, in non‐transgenic mice, we showed that WT tau or P301L tau does not form NFT while S320F tau can spontaneously aggregate into NFT, allowing us to test the selective vulnerability of these different tau conformations to the presence of Aβ plaques. Methods We injected recombinant AAV‐tau constructs into neonatal APP transgenic TgCRND8 mice or into 3‐month‐old TgCRND8 mice; both cohorts were aged 3 months post injection. This allowed us to test how different tau variants synergise with soluble forms of Aβ (pre‐deposit cohort) or with frank Aβ deposits (post‐deposit cohort). Results Expression of WT tau did not produce NFT or altered Aβ in either cohort. In the pre‐deposit cohort, S320F tau induced Aβ plaque deposition, neuroinflammation and synaptic abnormalities, suggesting that early tau tangles affect the amyloid cascade. In the post‐deposit cohort, contemporaneous expression of S320F tau did not exacerbate amyloid pathology, showing a dichotomy in Aβ‐tau synergy based on the nature of Aβ. P301L tau produced NFT‐type inclusions in the post‐deposit cohort, but not in the pre‐deposit cohort, indicating pathological synergy with pre‐existing Aβ deposits. Conclusions Our data show that different tau mutations representing specific folding variants of tau synergise with Aβ to different extents, depending on the presence of cerebral deposits.

IntroductionManagement of urachal anomalies in pediatric patients has historically lacked a clear consensus between conservative and surgical management. We aimed to review and summarize the literature on the diagnosis, symptoms, and evolution in the management of urachal anomalies in pediatric patients.MethodsWe performed a scoping literature review of PubMed/Medline and WebOfScience from January 2000 to February 2022.Results32 publications were selected for inclusion in this analysis. 1,438 unique studies were identified with 32 studies meeting inclusion criteria. 15/32 studies discussed both conservative and surgical management, 14/32 studies discussed only surgical management outcomes, and 3/32 studies discussed diagnostic methods. The studies discussing conservative management supported the treatment of urachal anomalies with an initial conservative approach, which includes watchful waiting, repeated ultrasounds, lesion measurement, and antibiotic use. 5/32 of the included studies identified patients that were converted from conservative to surgical management with conversion rates ranging from 12.5% to 43.5% per study. 14/20 converted patients were identified to have a urachal cyst and 13/20 had a persistent infection.ConclusionsStrong evidence exists that supports initial conservative management over surgical management of pediatric urachal anomalies. However, predictive factors for determining which patients will require surgical management remain elusive. Treatment algorithms can potentially be developed once carefully developed prospective studies delineate statistically significant patient factors which necessitate surgical management over observation.