Welcome to the AD/PD™ 2022 Interactive Program
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EARLIER ALZHEIMER'S DISEASE ONSET IS ASSOCIATED WITH A BIAS OF TAU PATHOLOGY TOWARDS BRAIN HUBS WHICH FACILITATES TAU SPREADING
Abstract
Aims
In Alzheimer’s disease (AD), younger symptom onset is associated faster cognitive decline and tau spreading, yet the drivers of faster disease manifestation are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto-parietal regions which harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading. Thus, we hypothesized that a bias of tau towards hubs may facilitate tau spreading and earlier symptom manifestation.
Methods
We included two independent samples with longitudinal Flortaucipir tau-PET covering the AD spectrum (ADNI: n(controls/AD-preclinical/AD-symptomatic)=93/60/89, BioFINDER, n(controls/AD-preclinical/AD-symptomatic)=16/16/25). In addition, we included resting-state fMRI from human connectome project participants (n=1000), applying a 200-ROI brain atlas to obtain a global connectivity gradient (Fig.1A-D). Applying the same atlas to tau-PET we transformed SUVRs to tau positivities using gaussian-mixture modeling (Fig.1E-F). By mapping tau-PET positivities to the global connectivity gradient (Fig.1G-L), we assessed whether tau-PET was biased towards hubs.
Results
In symptomatic AD, younger age was associated with a stronger bias of tau-PET towards hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]<0.001/0.001, Fig.2C&D). Younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger bias of tau-PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), suggesting that hubs facilitate tau spreading (Fig.3). Further, a stronger bias of tau-PET towards hubs mediated the association between younger age and faster tau accumulation in symptomatic AD (p[ADNI/BiOFINDER]=0.039/0.046).
Conclusions
Younger AD symptom onset is associated with stronger tau pathology in functional hubs, which facilitates tau spreading.
CYCLIC GMP-AMP SYNTHASE PROMOTES MICROGLIAL INTERFERON ACTIVATION AND COGNITIVE DEFICITS IN TAUOPATHY.
Abstract
Aims
Alzheimer’s disease (AD) is the most common form of late-onset dementia. The striking enrichment of innate immune genes as risk alleles for AD points to microglial and innate immune signaling as important players in AD pathogenesis. Antiviral response pathways, which are upregulated in AD, have emerged as important regulators of microglial disease responses including immune activation and synaptic pruning. However, the specific mediators of maladaptive antiviral microglial responses in AD are still not understood. There is emerging evidence that cyclic GMP-AMP synthase (cGAS) DNA-sensing pathway drives deleterious type-I interferon activation in various neurodegenerative diseases. The role of this pathway in tauopathies and AD pathogenesis remains unexplored.
Methods
We apply combinatorial approaches to determine the effects of partial and complete loss of cGAS in the pathogenesis of the P301S tauopathy model. We utilize in vitro culture platforms, transcriptomics, electrophysiological recordings and behavioral assays to investigate the roles of cGAS in tauopathy.
Results
We find that cGAS and interferon signaling are activated in the hippocampi of tauopathy mice and AD patients. Loss of cGAS protects tauopathy mice from synapse loss, synaptic plasticity deficits and cognitive impairment. Additionally, we find that pathogenic tau induces a cGAS-dependent interferon-enriched microglial subpopulation in mice at least partly by causing mitochondrial DNA leakage. Pharmaceutical inhibition of cGAS ameliorates tau-induced synapse loss and cognitive deficits.
Conclusions
cGAS promotes deleterious microglial interferon activation implicated in synaptic dysfunction and cognitive impairment in tauopathy. The promising results of pharmacological cGAS inhibition in tauopathy mice supports cGAS as a potential therapeutic target for treating AD.
CYTOSOLIC ANTIBODY RECEPTOR TRIM21 PROVIDES IMMUNOTHERAPEUTIC PROTECTION AGAINST TAU PATHOLOGY
Abstract
Aims
Antibodies represent one of the most promising therapeutic avenues against tau pathology in the near-term, yet the mechanisms by which they exert therapeutic protection remain uncertain. One possibility is that antibodies bind to tau assemblies in the extracellular spaces of the brain and prevent seeded aggregation of tau, thereby reducing the spread of tau pathology. Here, we aimed to understand the role of antibodies in blocking tau uptake to neurons and to discern the role of the intracellular environment in protection against tau pathology.
Methods
Tau entry to primary neurons was measured using luciferase complementation in real time. Seeded aggregation was measured in cell lines and organotypic slice culture. In vivo immunotherapy and targeted degradation were performed in P301S human tau transgenic mice.
Results
We found that tau assemblies transit to the cytosol of neurons in a process that is independent of clathrin endocytosis. Whilst some antibodies interfere with entry, others exert post-entry protection against seeded aggregation. Antibody-tau complexes that access the cytosol are bound by the atypical antibody receptor and E3 ubiquitin ligase Trim21, which mediates inactivation of tau seeding activity. In vivo, immunotherapeutic protection relied on Trim21, as Trim21-null mice were refractory to immunotherapy. Using these results, we designed novel Trim21-based proteins capable of promoting selective protein degradation in cell-based assays and in the brain.
Conclusions
Our results suggest that the cytosolic environment is available for immunotherapeutic protection against tau pathology. Future work should optimise antibodies and antibody-based degraders for enhanced targeting of cytosolic proteins in neurodegenerative disease.
SELECTION AND CHARACTERIZATION OF A NOVEL FULL LENGTH TAU TARGETING D-AMINO ACID PEPTIDE AS A POTENTIAL THERAPEUTIC APPROACH FOR ALZHEIMER’S DISEASE
Abstract
Aims
One of the pathological hallmarks of Alzheimer’s disease (AD) is abnormally aggregated Tau protein. We aimed to develop novel D-amino acid peptides as Tau aggregation inhibitors, that were selected against full length Tau. It has already been demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-amino acid peptides, what makes them suitable for possible in vivo applications. Binding of the D-peptides to Tau as a monomer or small oligomer could provide an early point of intervention in the pathological fibrillization cascade.
Methods
Using phage display against full-length Tau, we selected a novel Tau binding peptide, designated ISAD1. The D-peptides' ability in Tau binding and inhibition of Tau fibrilization was characterized using ELISA, ThT assays, dynamic light scattering, pelleting assays, in silico modeling and cell culture experiments.
Results
ISAD1 bound Tau in the PHF6 region and inhibited fibrillization of wild type Tau, diverse disease associated Tau mutants and a pro-aggregant repeat domain Tau mutant. In silico modelling of the D-amino acid peptide - Tau interaction suggested a similar binding mode to that known for other PHF6 binding peptides. ISAD1 induced the formation of large high molecular weight Tau aggregates that lack proper Thioflavin positive β-sheet conformation. Cell culture experiments demonstrated that ISAD1 is taken up by N2a cells efficiently and prevents cytotoxicity of externally added Tau fibrils.
Conclusions
Based on our results, it appears that ISAD1 could emerge as a promising therapy for early intervention of AD, presumably by inhibiting toxic Tau oligomer formation and promoting off-pathway assembly of Tau.
PROLYL OLIGOPEPTIDASE MODULATION REDUCES TAU LEVELS IN VIVO AND HAS DISEASE-MODIFYING EFFECTS IN TAU TRANSGENIC MOUSE
Abstract
Aims
We have earlier shown that prolyl oligopeptidase (PREP) negatively regulates protein phosphatase 2A (PP2A) via protein-protein interaction network and that a PREP inhibitor, KYP-2047, activates PP2A. PP2A is the main phosphatase dephosphorylating and stabilizing Tau, and it also activates autophagy and reduces ROS production. KYP-2047 has several beneficial effects in alpha-synuclein-based Parkinson’s disease models. Thus, we wanted to test if KYP-2047 and a novel PREP ligand, HUP-46, can attenuate Tau toxicity in vivo.
Methods
Tau transgenic mice (PS19) were characterized by using Barnes Maze memory test at 5 and 7 months of age. Memory deficits were visible after 5 months, and we initiated a 4-week treatment with KYP-2047 (IC50 0.2 nM) or HUP-46 (IC50 7 μM) with Alzet minipumps (i.p., 10 mg/kg) in 5.5-month-old mice. After the treatment period, memory was tested with Barnes Maze. Thereafter, total Tau and S262 phosphorylated Tau were detected by immunohistochemistry and CSF Tau by ELISA. PP2A, phosphorylated PP2A, p62, LC3B and 4-HNE were detected by Western blot.
Results
4-week treatment by KYP-2047 and HUP-46 restored normal behavior of PS19 mice in Barnes Maze. In hippocampus and cortex, total and S262 phosphorylated Tau were reduced to wild-type mouse levels. Western blot analysis revealed that pPP2A/PP2A ratio and autophagy markers, p62 and LC3B, were normalized following PREP ligand treatment. HUP-46 reduced Tau in CSF.
Conclusions
PREP modulation by small-molecular PREP ligands has disease-modifying effects in PS19 mouse although the treatment was initiated at symptom onset. Moreover, enzymatic PREP inhibition is not required for these actions.
CGX101, A TREM2 AGONISTIC MONOCLONAL ANTIBODY, ATTENUATES PHOPHO-TAU BURDEN AND NEURODEGENERATION IN EXPERIMENTAL TAUOPATHY
Abstract
Aims
TREM2 is a microglial receptor that plays an important role in shaping the response of the innate immune system to misfolded proteins. However, in the pathogenesis of Alzheimer's disease, Tau appears to play at least an equally important role. Data on the influence of TREM2 on Tau pathology is inconsistent. We have thus explored the effects of our agonistic anti-TREM2 mAb, CGX101 on Tau pathology in vitro, ex vivo and in vivo in different systems modeling phopho-Tau pathology.
Methods
Neuroinflammation (RT-PCR, protein-ARRAY), synaptic markers (synaptophysin), neurodegeneration (NeuN, Cresyl-violet, caspase3), neurofibrillary tangles and cognitive function (morris water maze) were assessed in mice treated with CGX101. Tau spreading and seeding (ex-vivo, tau transgenic primary neurons) and phospho-Tau mediated toxicity were tested in vitro and ex vivo in multiple protein and immunofluorescence assays.
Results
CGX101 was shown to protect neurons from phopho-Tau mediated toxicity and conditioned medium from antibody treated microglia attenuated spreading and seeding of tau pathology in vitro in Tau transgenic primary neurons. These effects of spreading and seeding were also evident in an organoid system comprising slides of brains from mice with a dual human Tau mutation. In vivo, CGX101 treated wild type mice intracerebrally inoculated with pTau, exhibited inhibition of propagation and spreading of phospho-Tau pathology to the contralateral hemisphere. Finally, in vivo treatment with CGX101 ameliorated cognitive decline, aggregated phospho-Tau burden and neurodegeneration while facilitating synaptic preservation in hTau transgenic mice.
Conclusions
CGX101 is the first TREM2 agonist to exhibit a robust beneficial effect on neurodegeneration and Tau load in experimental tauopathy, via microglial priming.
PRE-RECORDED: ASSESSMENT OF SAFETY, TOLERABILITY, AND EFFICACY OF ZAGOTENEMAB: RESULTS FROM PERISCOPE-ALZ, A PHASE 2 STUDY IN EARLY SYMPTOMATIC ALZHEIMER’S DISEASE
Abstract
Aims
Zagotenemab (LY3303560), a monoclonal antibody targeting extracellular aggregated tau was assessed in the PERISCOPE-ALZ Phase 2 study (NCT03518073) to determine its ability to slow cognitive and functional decline relative in early symptomatic Alzheimer’s disease (AD).
Methods
Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Exam score of 20-28, and intermediate levels of brain tau. In this double-blind study, participants were equally randomized to one of two doses of zagotenemab, or placebo (intravenous infusion every 4 weeks for 100 weeks). The primary outcome measure was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model.
Results
Three-hundred, sixty participants were randomized; 218 completed the treatment period. Demographics and baseline characteristics were balanced among treatment arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for iADRS was 1.10 (0.959, 1.265) for the zagotenemab low dose group and 1.05 (0.907, 1.209) for the high dose, where a ratio less than 1 favors the treatment group. Secondary endpoint measures of cognition/function failed to show a drug-placebo difference in favor of active treatment. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analysis. Safety data will be reported.
Conclusions
In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression. Imaging biomarker and NfL findings did not show evidence of pharmacodynamic activity or disease modification.