Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay. Methods We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology, synaptic transmission, and behavior. Results The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI. Conclusion In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.

The triggers for the development of multiple sclerosis (MS) have not been fully understood to date. One hypothesis proposes a viral etiology. Interestingly, viral proteins from human endogenous retroviruses (HERVs) may play a role in the pathogenesis of MS. Allelic variants of the HERV-K18 env gene represent a genetic risk factor for MS, and the envelope protein is considered to be an Epstein–Barr virus-trans-activated superantigen. To further specify a possible role for HERV-K18 in MS, the present study examined the immunogenicity of the purified surface unit (SU). HERV-K18(SU) induced envelope-specific plasma IgG in immunized mice and triggered proliferation of T cells isolated from these mice. It did not trigger phenotypic changes in a mouse model of experimental autoimmune encephalomyelitis. Further studies are needed to investigate the underlying mechanisms of HERV-K18 interaction with immune system regulators in more detail.

BackgroundPyroglutamate‐3Aβ (N3pE), a toxic Aβ variant formed by the activity of glutaminyl gyclase (QPCT) has been shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). Recently, we demonstrated that a combination of the QPCT inhibitor varoglutamstat (PQ912) with the N3pE‐specific antibody m6 has an additive effect on lowering of N3pE in vivo. Here, we analyzed whether a similar additive effect could be achieved when combining varoglutamstat with the Aβ‐aggregate‐specific antibody aducanumab.MethodNine‐months old APPxhQC mice were treated with either varoglutamstat (1.6 g/kg chow, ad libitum), chimeric aducanumab (chAdu, ≈10 mg/kg i.p. weekly) or a combination of both for 16 weeks. Brain Aβ accumulation (ELISA and immunohistochemistry) and AD biomarkers in the water‐soluble brain fractions (neurogranin, BACE‐1, YKL‐40; ELISA) were analyzed and compared to a vehicle‐treated group.ResultTreatment with either varoglutamstat or chAdu significantly reduced the accumulation of both total Aβ and N3pE in the brain. The effect of chAdu was more pronounced for total Aβ (‐35% vs. ‐21% for varoglutamstat), while varoglutamstat treatment resulted in a stronger decrease of N3pE (‐28% vs. ‐19% for chAdu). The combination treatment generally led to a stronger decrease of Aβ vs. single agent treatment (Bliss combination index (CI) = 0.88 for soluble Aβ42 and 1.23 for insoluble Aβ42). For insoluble N3pE, the observed effect was nearly additive (CI = 1.09). Treatment with chAdu, varoglutamstat or both had different effects on the analyzed AD biomarkers. chAdu treatment significantly decreased BACE‐1 protein levels (‐30%), while varoglutamstat treatment significantly reduced levels of the brain inflammation marker YKL‐40 (‐27%), which is in line with earlier clinical Phase 2a study results.ConclusionOur data indicate that a combination of agents with different modes of action such as aducanumab, an Aβ aggregate‐specific antibody and varoglutamstat, a small molecule designed to block formation of toxic, aggregation‐prone N3pE, can act additively to decrease total Aβ and N3pE levels in the brain. Our results also provide a rationale for investigating different potential combination regimens, including an initial antibody‐mediated Aβ clearance followed by long‐term suppression of N3pE formation and inflammation by varoglutamstat (“treat and maintain”).

Passive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). Among the different antibodies under development, those targeting post-translationally modified Aβ peptides might combine efficient reduction in beta-amyloid accompanied by lower sequestration in peripheral compartments and thus anticipated and reduced treatment-related side effects. In that regard, we recently demonstrated that the antibody-mediated targeting of isoD7-modified Aβ peptides leads to the attenuation of AD-like amyloid pathology in 5xFAD mice. In order to assess novel strategies to enhance the efficacy of passive vaccination approaches, we investigated the role of CD33 for Aβ phagocytosis in transgenic mice treated with an isoD7-Aβ antibody. We crossbred 5xFAD transgenic mice with CD33 knock out (CD33KO) mice and compared the amyloid pathology in the different genotypes of the crossbreds. The knockout of CD33 in 5xFAD mice leads to a significant reduction in Aβ plaques and concomitant rescue of behavioral deficits. Passive immunotherapy of 5xFAD/CD33KO showed a significant increase in plaque-surrounding microglia compared to 5xFAD treated with the antibody. Additionally, we observed a stronger lowering of Aβ plaque load after passive immunotherapy in 5xFAD/CD33KO mice. The data suggest an additive effect of passive immunotherapy and CD33KO in terms of lowering Aβ pathology. Hence, a combination of CD33 antagonists and monoclonal antibodies might represent a strategy to enhance efficacy of passive immunotherapy in AD.

Background Passive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). We recently demonstrated that the antibody‐mediated targeting of isoD7‐modified Aβ peptides leads to the attenuation of AD‐like amyloid pathology in 5xFAD mice (Gnoth et al., 2020). Targeting post‐translationally modified Aβ peptides is a promising approach for reduction of effective therapeutic antibody amount and thereby decreasing treatment‐related side effects. Nevertheless, high dosing of monoclonal antibodies and appearance of side effects such as amyloid‐related imaging abnormalities (ARIAs) provide room for approaches such as combination therapies. Method We investigated the role of CD33 for Aβ phagocytosis in transgenic mice treated with an isoD7‐Aβ antibody. CD33 or sialic‐acid‐binding immunoglobulin‐like lectin 3 (Siglec‐3) is an inhibitory receptor molecule on the surface of brain microglia. We generated a new mouse line by crossing 5xFAD mice (Oakley et al., 2006) with CD33 knock out mice (Brinkman‐Van der Linden et al., 2003). This mouse line was then used for treatment studies with our anti‐isoD7‐Aβ antibody K11_IgG2a. Therefore, 3month‐old female 5xFAD and 5xFAD/CD33 mice were treated with 4 mg/kg K11_IgG2a and IgG2a isotype control. After 38 weeks treatment an Elevated Plus Maze (EPM) test have been performed, followed by the preparation of mouse brain and the read out by ELISA and Immunohistochemistry. Result We could demonstrate that CD33 knock out leads to the reduction of Aβ plaque load as well as the rescue of behavioral deficits in 5xFAD mice. Above that, we detected elevated amounts of plaque surrounding microglia in 5xFAD/CD33KO mice receiving antibody treatment, followed by an even more decrease of Aβ plaque load. Conclusion In summary, a combinational therapy, concomitantly targeting post‐translational modified Aβ peptides and CD33, leads to an add‐on effect in passive immunotherapy.