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With increased research funding for Alzheimer’s disease (AD) and related disorders across the globe, large amounts of data are being generated. Several studies employed machine learning methods to understand the ever-growing omics data to enhance early diagnosis, map complex disease networks, or uncover potential drug targets. We describe results based on a Target Central Resource Database protein knowledge graph and evidence paths transformed into vectors by metapath matching. We extracted features between specific genes and diseases, then trained and optimized our model using XGBoost, termed MPxgb(AD). To determine our MPxgb(AD) prediction performance, we examined the top twenty predicted genes through an experimental screening pipeline. Our analysis identified potential AD risk genes: FRRS1, CTRAM, SCGB3A1, FAM92B/CIBAR2 , and TMEFF2 . FRRS1 and FAM92B are considered dark genes, while CTRAM , SCGB3A1 , and TMEFF2 are connected to TREM2-TYROBP, IL-1β-TNFα, and MTOR-APP AD-risk nodes, suggesting relevance to the pathogenesis of AD. Jessica Binder et al. developed a machine learning model to discover potential drug targets for Alzheimer’s disease. They validated their 20 top candidates in several in vitro models, and highlight FRRS1 , CTRAM , SCGB3A1 , FAM92B/CIBAR2 , and TMEFF2 as potential AD risk genes.

Tauopathies, including Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapy development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and inflammatory microgliosis in a 4.5-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapies.

INTRODUCTION Pathological accumulation of tau (pTau) contributes to various tauopathies, including Alzheimer's disease (AD), and correlates with cognitive decline. A rapid surge in tau‐targeted approaches via anti‐sense oligonucleotides, active/passive immunotherapies suggests that targeting p‐Tau is a viable strategy against tauopathies. METHOD We describe a multi‐species validation of our previously described Qß virus‐like particle (VLP)–based vaccine technology targeting phosphorylated tau on threonine 181 (pT181‐Qß). RESULTS Two vaccine doses of pT181‐Qß, without any adjuvants, elicited robust antibody responses in two different mouse models of tauopathy (PS19 and hTau) and rhesus macaques. In mouse models, vaccination reduced AT180+ hyperphosphorylated, Sarkosyl insoluble, Gallyas silver positive tau, inflammasomes/neuroinflammation, and improved recognition memory and motor function without inducing adverse T‐cell activation. Anti‐pT181 antibodies are reactive to pTau in human AD brains, engage pT181+ tau in human brain lysates, and are central nervous system bioavailable. DISCUSSION Our results suggest the translational utility of pT181‐Qß against tauopathies. Highlights Icosahedral display of phosphorylated tau at threonine 181 (pT181) Qß virus‐like particle surface (“pT181‐Qß” vaccine) induces a robust immune response in mice and in non‐human primates (NHPs) pT181‐Qß vaccination reduces pathological tau (pTau) and brain atrophy, and improves memory and motor function in PS19 and hTau mice. pT181‐Qß vaccination–induced immunoglobulin Gs (IgGs) are safe, Th2 skewed (anti‐inflammatory), specific to pTau in human AD brain, and efficiently engage pT181 in NHPs and human brain lysate. pT181+ tau in human plasma correlates with the neurofilament light in subjects with mild cognitive impairment (MCI)—suggesting the presence of pT181‐Qß vaccine target in the early disease state.

Background Fractalkine (CX 3 CL1) and its receptor (CX 3 CR1) play an important role in regulating microglial function. We have previously shown that Cx 3 cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX 3 CL1 is essential in regulating neuronal tau pathology. Methods We used transgenic mice lacking endogenous Cx 3 cl 1 ( Cx 3 cl1 −/− ) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX 3 CL1 (referred to as Cx 3 cl1 105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. Results First, increased basal tau levels accompanied microglial activation in Cx 3 cl1 105Δ mice compared to control groups. Second, increased CD45 + and F4/80 + neuroinflammation and tau phosphorylation were observed in LPS, hTau/ Cx 3 cl1 −/− , and hTau/ Cx 3 cl1 105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX 3 CR1 was reduced in Cx 3 cl1 105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx 3 cr1 deletion), which likely contributes to the elevated tau pathology. Conclusions Collectively, our data suggest that overexpression of only chemokine domain of CX 3 CL1 does not protect against tau pathology.

Increasing evidence suggests that hyperphosphorylation and aggregation of microtubule-associated protein tau (MAPT or tau) correlates with the development of cognitive impairment in Alzheimer's disease (AD) and related tauopathies. While numerous attempts have been made to model AD-relevant tau pathology in various animal models, there has been very limited success for these models to fully recapitulate the progression of disease as seen in human tauopathies. Here, we performed whole genome gene expression in a genomic mouse model of tauopathy that expressed human gene under the control of endogenous human promoter and also were complete knockout for endogenous mouse tau [referred to as 'hTau ' mice]. First, whole genome expression analysis revealed 64 genes, which were differentially expressed (32 up-regulated and 32 down-regulated) in the hippocampus of 6-month-old hTau mice compared to age-matched non-transgenic controls. Genes relevant to neuronal function or neurological disease include up-regulated genes: PKC-alpha ( ), MECP2 ( ), STRN4 ( ), SLC40a1 ( ), POLD2 ( ), PCSK2 ( ), and down-regulated genes: KRT12 ( ), LASS1 ( ), PLAT ( ), and NRXN1 ( ). Second, network analysis suggested anatomical structure development, cellular metabolic process, cell death, signal transduction, and stress response were significantly altered biological processes in the hTau mice as compared to age-matched non-transgenic controls. Further characterization of a sub-group of significantly altered genes revealed elevated phosphorylation of MECP2 (methyl-CpG-binding protein-2), which binds to methylated CpGs and associates with chromatin, in hTau mice compared to age-matched controls. Third, phoshpho-MECP2 was elevated in autopsy brain samples from human AD compared to healthy controls. Finally, siRNA-mediated knockdown of MECP2 in human tau expressing N2a cells resulted in a significant decrease in total and phosphorylated tau. Together, these results suggest that MECP2 is a potential novel regulator of tau pathology relevant to AD and tauopathies.

Tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are progressive neurodegenerative diseases clinically characterized by cognitive decline and could be caused by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles (NFTs) inside neurons. There is currently no FDA-approved treatment that cures, slows or prevents tauopathies. Current immunotherapy strategies targeting pTau have generated encouraging data but may pose concerns about scalability, affordability, and efficacy. Here, we engineered a virus-like particle (VLP)-based vaccine in which tau peptide, phosphorylated at threonine 181, was linked at high valency to Qß bacteriophage VLPs (pT181-Qß). We demonstrate that vaccination with pT181-Qß is sufficient to induce a robust and long-lived anti-pT181 antibody response in the sera and the brains of both Non-Tg and rTg4510 mice. Only sera from pT181-Qß vaccinated mice are reactive to classical somatodendritic pTau in human FTD and AD post-mortem brain sections. Finally, we demonstrate that pT181-Qß vaccination reduces both soluble and insoluble species of hyperphosphorylated pTau in the hippocampus and cortex, avoids a Th1-mediated pro-inflammatory cell response, prevents hippocampal and corpus callosum atrophy and rescues cognitive dysfunction in a 4-month-old rTg4510 mouse model of FTD. These studies provide a valid scientific premise for the development of VLP-based immunotherapy to target pTau and potentially prevent Alzheimer’s diseases and related tauopathies. Tauopathies: Active vaccination of mouse tauopathy Tauopathies such as fronto-temporal dementia or Alzheimer’s disease are characterized by the accumulation of phosphorylated Tau (pTau) protein into pathogenic neurofibrillary tangles (NFT). Kiran Bhaskar and colleagues at the University of New Mexico investigate the efficacy of an active vaccine approach in the treatment of rTg4510 mice—an aggressive model of tauopathy. Mice receive 3 intramuscular doses of a disease-relevant pTau peptide (pT181) multivalently conjugated to an immunostimulatory bacteriophage virus-like particle (pT181-Qß). Vaccination induces high titers of anti-pTau—stable to at least 20 weeks—that is also able to bind human disease samples, but importantly does not react to unphosphorylated physiological Tau protein. Antibody can enter the brain and bind both soluble and intraneuronal pTau. Vaccination of mice reduces brain NFT, pathology, indicators of neuroinflammation and improves cognitive function in two different models of memory.

The identification of protein aggregates as biomarkers for neurodegeneration is an area of interest for disease diagnosis and treatment development. In this work, we present novel super luminescent conjugated polyelectrolyte molecules as ex vivo sensors for tau-paired helical filaments (PHFs) and amyloid-β (Aβ) plaques. We evaluated the use of two oligo-p-phenylene ethynylenes (OPEs), anionic OPE12− and cationic OPE24+, as stains for fibrillar protein pathology in brain sections of transgenic mouse (rTg4510) and rat (TgF344-AD) models of Alzheimer’s disease (AD) tauopathy, and post-mortem brain sections from human frontotemporal dementia (FTD). OPE12− displayed selectivity for PHFs in fluorimetry assays and strong staining of neurofibrillary tangles (NFTs) in mouse and human brain tissue sections, while OPE24+ stained both NFTs and Aβ plaques. Both OPEs stained the brain sections with limited background or non-specific staining. This novel family of sensors outperformed the gold-standard dye Thioflavin T in sensing capacities and co-stained with conventional phosphorylated tau (AT180) and Aβ (4G8) antibodies. As the OPEs readily bind protein amyloids in vitro and ex vivo, they are selective and rapid tools for identifying proteopathic inclusions relevant to AD. Such OPEs can be useful in understanding pathogenesis and in creating in vivo diagnostically relevant detection tools for neurodegenerative diseases.

Background Hyperphosphorylation and aggregation of neuronal tau protein is a primary pathological hallmark of Alzheimer’s disease (AD) and primary tauopathies. The accumulation of aggregated tau as neurofibrillary tangles (NFTs) is closely correlated with neurodegeneration and cognitive decline. Key phosphorylation sites on tau have been established as early biomarkers for disease detection and prediction, with various phosphorylation sites differentially appearing across diseases and disease stages. These phosphorylation sites may serve as valuable therapeutic targets for immunotherapeutic development with but with variable efficacy. Method Human hippocampal brain tissue sections from Alzheimer’s disease and several primary tauopathies were immunostained using either commercial antibodies targeting specific phosphorylation sites on tau, or with immune sera obtained from mice vaccinated using a Qβ virus‐like particle (VLP) platform targeting identical tau phosphorylation sites. Immune sera were from twice vaccinated rTg4510, P301S, or C57Bl/6j mice undergoing therapeutic vaccine trials 6‐8 weeks after their first vaccination, with booster vaccinations administered two weeks apart. The vaccines used targeted the T181, S199/S202, T217, and S396/S404 tau phosphorylation sites. Immune sera were pooled from n = 5 animals each and diluted 1:500 for staining human hippocampal sections. AT8, PHF1, AT270, and Thr217 antibodies were used to compare tau histopathology. Sections were immunostained and tau visualization was performed using diaminobenzidine (DAB). Result Immune sera from animals vaccinated with each tau vaccine successfully detected tau pathology across disease tissues similarly to commercially available antibodies. However, the range of histopathological features detected by each vaccine differed from each other within disease tissues and across diseases. Differences included detection of unique tau pathological features like neuropil threads, neuritic plaques, immature and mature NFTs, Pick bodies, and tau‐positive glial cells. Conclusion Tau vaccines targeting various tau phosphorylation epitopes show differential recognition of tau pathology within and across brain tissue sections from Alzheimer’s disease and primary tauopathies.

Background Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1. Method We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice. Results First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 (pS199/pS202) site tau phosphorylation, with the maximum effect peaking at 60–90 min after stimulation. Second, treatment of old (~20 months of age) hTau mice with MW181 (1 mg/kg body weight; 14 days via oral gavage) significantly reduced p38α MAPK activation compared with vehicle-administered hTau mice. This also resulted in a significant reduction in AT180 (pT231) site tau phosphorylation and Sarkosyl-insoluble tau aggregates. Third, MW181 treatment significantly increased synaptophysin protein expression and resulted in improved working memory. Fourth, MW181 administration reduced phosphorylated MAPK-activated protein kinase 2 (pMK2) and phosphorylated activating transcription factor 2 (pATF2), which are known substrates of p38α MAPK. Finally, MW181 reduced the expression of interferon-γ and interleukin-1β. Conclusions Taken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.

Neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia spatially coexist with microtubule-associated protein tau (Mapt or tau)-burdened neurons in the brains of human AD and non-AD tauopathies. Numerous studies have suggested that neuroinflammation precedes tau pathology and that induction or blockage of neuroinflammation via lipopolysaccharide (LPS) or anti-inflammatory compounds (such as FK506) accelerate or block tau pathology, respectively in several animal models of tauopathy. We have previously demonstrated that microglia-mediated neuroinflammation via deficiency of the microglia-specific chemokine (fractalkine) receptor, CX3CR1, promotes tau pathology and neurodegeneration in a mouse model of LPS-induced systemic inflammation. Here, we demonstrate that tau mediates the neurotoxic effects of LPS in Cx3cr1 (-/-) mice. First, Mapt (+/+) neurons displayed elevated levels of Annexin V (A5) and TUNEL (markers of neurodegeneration) when co-cultured with LPS-treated Cx3cr1 (-/-)microglia, which is rescued in Mapt (-/-) neurons. Second, a neuronal population positive for phospho-S199 (AT8) tau in the dentate gyrus is also positive for activated or cleaved caspase (CC3) in the LPS-treated Cx3cr1 (-/-) mice. Third, genetic deficiency for tau in Cx3cr1 (-/-) mice resulted in reduced microglial activation, altered expression of inflammatory genes and a significant reduction in the number of neurons positive for CC3 compared to Cx3cr1 (-/-)mice. Finally, Cx3cr1 (-/-)mice exposed to LPS displayed a lack of inhibition in an open field exploratory behavioral test, which is rescued by tau deficiency. Taken together, our results suggest that pathological alterations in tau mediate inflammation-induced neurotoxicity and that deficiency of Mapt is neuroprotective. Thus, therapeutic approaches toward either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.