Spread Of Tau Pathology Research Articles

Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure

Extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer’s disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aβ plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aβ and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aβ plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process.

PRX005, a novel anti‐MTBR tau monoclonal antibody: results from a first‐in‐human double‐blind, placebo‐controlled, single ascending dose phase 1 study

AbstractBackgroundMultiple lines of evidence indicate that tau protein spreads throughout the brain via synaptically connected pathways and that this propagation could be mediated by tau “seeds” containing the microtubule binding region (MTBR) of tau. In addition, cerebrospinal fluid (CSF) MTBR‐tau levels correlate with tau tangles and clinical stages of Alzheimer’s disease. To block the spread of tau pathology, we developed PRX005, a humanized monoclonal tri‐epitopic antibody that binds with high affinity to the R1, R2, and R3 repeats in the MTBR region of tau, and targets both 3R and 4R tau isoforms.MethodHealthy volunteers were randomly assigned to three dose cohorts and randomized in a 3:1 manner to receive either PRX005 or placebo. Primary endpoint was safety and tolerability with up to 2 months of follow‐up. Secondary endpoints included PRX005 pharmacokinetic parameters in plasma and CSF penetrance.ResultA total of 19 healthy volunteer participants received study drug or placebo. PRX005 was well tolerated and had a pharmacokinetic profile typical of IgG1 antibodies, with dose‐proportional increase in plasma concentration and central nervous system (CNS) penetrance. No persistent drug‐induced anti‐drug antibodies were observed following treatment with PRX005. Additional results from this Phase 1 will be presented.ConclusionIn this first‐in‐human, single ascending dose study, PRX005 was well tolerated and achieved CNS concentrations for pharmacological targeting of MTBR‐tau. Our results support the progression of the clinical development of PRX005 in an ongoing, multiple ascending dose study in patients with Alzheimer’s disease.

Prophylactic effect of passive immunotherapy with tau antibody 43D in 3xTg‐AD mice

AbstractBackgroundAccumulation of abnormally hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Immunotherapy targeting tau represents a promising disease‐modifying therapeutic strategy for treating AD. We have found that immunization with monoclonal 43D antibody against tau 6‐18 weekly for 6 weeks can inhibit the seeding and spread of tau pathology templated by AD hyperphosphorylated tau, reduce both tau and Aβ pathologies and rescue cognitive impairment in 3xTg‐AD mice at mild to moderate stage of the disease. In this study, we investigated whether tau immunization with 43D prior to the onset of AD‐like pathologies can reduce AD‐like pathologies and improve cognitive function in 3xTg‐AD mice.MethodsWe immunized 3‐ to 4‐month‐old female 3×Tg‐AD mice with nine monthly doses of 15 µg of mouse monoclonal antibody 43D or, as a control, of mouse immunoglobulin G (IgG) intravenously. Age‐matched wild‐type mice treated with mouse IgG were also used as controls. The effect of immunization on cognition was analyzed by using one‐trial novel object recognition test and Morris water maze test, and the effect on tau pathology was assessed by Western blot.ResultsWe found that 3xTg‐AD mice exhibited cognitive impairment as compared to the WT mice, as determined by novel object recognition test and Morris water maze test, and that immunization with 43D antibody improved the cognitive function seen in both tests. Immunization with 43D also decreased tau pathologies in the 3xTg‐AD mice. Additionally, long‐term treatment with 43D antibody did not display side events in 3xTg‐AD mice.ConclusionsThese findings suggest that passive immunization with 43D antibody targeting proximal N‐terminal domain tau 6‐18 may be as both prophylactic and therapeutic approaches for treating AD and related tauopathies.

ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels

For the Alzheimer disease (AD) therapies to effectively attenuate clinical progression, it may be critical to intervene before the onset of amyloid-associated tau spreading, which drives neurodegeneration and cognitive decline. Time points at which amyloid-associated tau spreading accelerates may depend on individual risk factors, such as apolipoprotein E ε4 (ApoE4) carriership, which is linked to faster disease progression; however, the association of ApoE4 with amyloid-related tau spreading is unclear. To assess if ApoE4 carriers show accelerated amyloid-related tau spreading and propose amyloid positron emission tomography (PET) thresholds at which tau spreading accelerates in ApoE4 carriers vs noncarriers. This cohort study including combined ApoE genotyping, amyloid PET, and longitudinal tau PET from 2 independent samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 237; collected from April 2015 to August 2022) and Avid-A05 (n = 130; collected from December 2013 to July 2017) with a mean (SD) tau PET follow-up time of 1.9 (0.96) years in ADNI and 1.4 (0.23) years in Avid-A05. ADNI is an observational multicenter Alzheimer disease neuroimaging initiative and Avid-A05 an observational clinical trial. Participants classified as cognitively normal (152 in ADNI and 77 in Avid-A05) or mildly cognitively impaired (107 in ADNI and 53 in Avid-A05) were selected based on ApoE genotyping, amyloid-PET, and longitudinal tau PET data availability. Participants with ApoE ε2/ε4 genotype or classified as having dementia were excluded. Resting-state functional magnetic resonance imaging connectivity templates were based on 42 healthy participants in ADNI. Mediation of amyloid PET on the association between ApoE4 status and subsequent tau PET increase through Braak stage regions and interaction between ApoE4 status and amyloid PET with annual tau PET increase through Braak stage regions and connectivity-based spreading stages (tau epicenter connectivity ranked regions). The mean (SD) age was 73.9 (7.35) years among the 237 ADNI participants and 70.2 (9.7) years among the 130 Avid-A05 participants. A total of 107 individuals in ADNI (45.1%) and 45 in Avid-A05 (34.6%) were ApoE4 carriers. Across both samples, we found that higher amyloid PET-mediated ApoE4-related tau PET increased globally (ADNI b, 0.15; 95% CI, 0.05-0.28; P = .001 and Avid-A05 b, 0.33; 95% CI, 0.14-0.54; P < .001) and in earlier Braak regions. Further, we found a significant association between ApoE4 status by amyloid PET interaction and annual tau PET increases consistently through early Braak- and connectivity-based stages where amyloid-related tau accumulation was accelerated in ApoE4carriers vs noncarriers at lower centiloid thresholds, corrected for age and sex. The findings in this study indicate that amyloid-related tau accumulation was accelerated in ApoE4 carriers at lower amyloid levels, suggesting that ApoE4 may facilitate earlier amyloid-driven tau spreading across connected brain regions. Possible therapeutic implications might be further investigated to determine when best to prevent tau spreading and thus cognitive decline depending on ApoE4 status.

Genetic and sporadic forms of tauopathies-TAU as a disease driver for the majority of patients but the minority of tauopathies.

Ageing-associated tauopathies like frontotemporal dementia (FTD), variants thereof (like progressive supranuclear palsy (PSP), pick diseases (PiD), corticobasal degeneration (CBD)), and of course the most prevalent form of dementia, Alzheimer Disease (AD), are widely recognized forms of tauopathies. The list of tauopathies is expanding. We now include: (i) tauopathies where the disease cause or trigger is clearly either physical, such as in Traumatic Brain Injury (TBI) or Chronic Traumatic Encephalopathy (CTE), and (ii) genetic diseases that result in tauopathy but have pathogenic genetic variants in genes not related to TAU. Examples of the latter are myotonic dystrophy Type 1 and Type 2 (DM1, DM2, due to pathogenic genetic variants in the genes DMPK and CNBP, respectively), Niemann-Pick Disease Type C (NPD, due to mutations in NPC1 or NPC2), Kufs Disease (CLN6), Christianson Syndrome (SLC9A6), familial forms of Parkinson Disease (PD), and many others. In terms of affected brain regions and cell types, intracellular distribution of TAU pathology/aggregates, age of disease onset, velocity of disease progression and spreading of TAU pathology, there is, however, little in common in most of these disease entities. Here, I reason that TAU/MAPT is causative for the minority of tauopathies (e.g., MAPT-related FTD/PSP and Vacuolar Tauopathy (VCP)) and a critical mediator for others, like shown by overwhelming evidence for AD. However, TAU may also be a mere bystander or even protective in other settings. Improved understanding of rare tauopathies is necessary to develop specific treatments, but also to improve our understanding of the pathomechanistic role of TAU and to identify diseases that may profit from TAU-based therapies.

Emerging Roles of Cells and Molecules of Innate Immunity in Alzheimer's Disease.

The inflammatory response that marks Alzheimer's disease (neuroinflammation) is considered a double-edged sword. Microglia have been shown to play a protective role at the beginning of the disease. Still, persistent harmful stimuli further activate microglia, inducing an exacerbating inflammatory process which impairs β-amyloid peptide clearance capability and leads to neurotoxicity and neurodegeneration. Moreover, microglia also appear to be closely involved in the spread of tau pathology. Soluble TREM2 also represents a crucial player in the neuroinflammatory processes. Elevated levels of TREM2 in cerebrospinal fluid have been associated with increased amyloid plaque burden, neurodegeneration, and cognitive decline in individuals with Alzheimer's disease. Understanding the intricate relationship between innate immunity and Alzheimer's disease will be a promising strategy for future advancements in diagnosis and new therapeutic interventions targeting innate immunity, by modulating its activity. Still, additional and more robust studies are needed to translate these findings into effective treatments. In this review, we focus on the role of cells (microglia, astrocytes, and oligodendrocytes) and molecules (TREM2, tau, and β-amyloid) of the innate immune system in the pathogenesis of Alzheimer's disease and their possible exploitation as disease biomarkers and targets of therapeutical approaches.

Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology

Tau deposits in astrocytes are frequently found in Alzheimer’s disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

The Adult Neurogenesis Theory of Alzheimer's Disease.

Alzheimer's disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this "reactive" pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission.

Extended insight into selective vulnerability of neurons in AD using machine learning approach

AbstractBackgroundAlzheimer’s disease is characterized by the spread of tau pathology and loss of neurons with a specific spatio‐temporal pattern. Recent publications have attempted to uncover the identity of the selectively vulnerable neurons using single‐nucleus transcriptomic data derived from affected brain regions from patients with Alzheimer’s disease. Correlating advancing tau pathology as measured by Braak staging with neuronal loss, one of the major markers reported for the susceptible excitatory neurons was RORB, which was also validated using quantitative neuropathological methods. However, the heterogeneity of RORB expression in the highlighted clusters suggested that not all RORB expressing neurons may be susceptible. Besides, further classifying neuronal population into sub‐populations shows population specific RORB expression.MethodTherefore, we further extended our insight into selective vulnerability of neuronal sub‐populations using a machine learning (ML) approach. We identified a transcriptionally homogeneous population using ML‐based classifiers with high accuracy and AUC &gt; 0.90.ResultOur analysis shows that fine mapping of transcriptionally similar neurons is key to pinpoint sub‐populations that are selectively lost during later Braak stages. For instance, refined sub‐population analysis revealed that neuronal populations with moderate RORB expression were lost while those with higher RORB expression do not show significant change with advancing Braak stage.ConclusionOur analysis provides a reference of neuronal sub‐populations and associated markers that could be further interrogated to uncover potential mechanisms that underlie selective degeneration in Alzheimer’s Disease.

A joint model of network spread and selective vulnerability explains tau pathology spread in Alzheimer’s disease mouse models

AbstractBackgroundThe propagation and spread of pathology in Alzheimer’s disease (AD) results from the interplay of many complex biological processes. Two key hypotheses have been proposed to help explain the characteristic Braak stageing patterns that define typical AD tau pathology1: network spread, which posits that trans‐synaptic spread of tau determines how pathology progresses2, and selective vulnerability, which states that the regions most affected by tau pathology contain high densities of cell types particularly sensitive to the presence of tau3. Here we explore the explanatory power of each hypothesis in the context of mouse tauopathy models.MethodsWe implemented a mathematical network spread model that extends the Network Diffusion Model2 by adding a linear accumulation term (sNDM). We also utilized the cell type distributions recently made available by the MISS algorithm, which deconvolves spatial transcriptomic data into cell type densities using scRNAseq information4. We fit the sNDM to the Iba, et al. PS19 tauopathy model seeded at the hippocampus5 (IbaHippInj) and the Hurtado, et al. unseeded PS19/PDAPP model6 (Hurtado).ResultsWe find that although network spread is the single‐best correlate of tau pathology, there are many cell types that are highly correlated at the regional level, particularly Layer‐2/3 glutamatergic neurons and Lamp5‐expressing GABAergic neurons (Figure 1). A combined linear model using sNDM predictions and these two cell types (Figure 2) yields higher R2 values than the sNDM predictions alone (Figure 3).ConclusionWe demonstrate that both the network spread and selective vulnerability hypotheses contribute meaningful information for explaining tau pathology in mouse models, indicating that more sophisticated modeling approaches taking into account the full biological complexity of AD have more explanatory power.

Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1.

HS3ST1 is a genetic risk gene associated with Alzheimer's disease (AD) and overexpressed in patients, but how it contributes to the disease progression is unknown. We report the analysis of brain heparan sulfate (HS) from AD and other tauopathies using a LC-MS/MS method. A specific 3-O-sulfated HS displayed sevenfold increase in the AD group (n = 14, P < 0.0005). Analysis of the HS modified by recombinant sulfotransferases and HS from genetic knockout mice revealed that the specific 3-O-sulfated HS is made by 3-O-sulfotransferase isoform 1 (3-OST-1), which is encoded by the HS3ST1 gene. A synthetic tetradecasaccharide (14-mer) carrying the specific 3-O-sulfated domain displayed stronger inhibition for tau internalization than a 14-mer without the domain, suggesting that the 3-O-sulfated HS is used in tau cellular uptake. Our findings suggest that the overexpression of HS3ST1 gene may enhance the spread of tau pathology, uncovering a previously unidentified therapeutic target for AD.

Synaptic oligomeric tau in Alzheimer’s disease — A potential culprit in the spread of tau pathology through the brain

In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads trans-synaptically from pre- to postsynapses and that oligomeric tau is synaptotoxic, but data on synaptic tau in human brain are scarce. Here we used sub-diffraction-limit microscopy to study synaptic tau accumulation in postmortem temporal and occipital cortices of human Alzheimer's and control donors. Oligomeric tau is present in pre- and postsynaptic terminals, even in areas without abundant fibrillar tau deposition. Furthermore, there is a higher proportion of oligomeric tau compared with phosphorylated or misfolded tau found at synaptic terminals. These data suggest that accumulation of oligomeric tau in synapses is an early event in pathogenesis and that tau pathology may progress through the brain via trans-synaptic spread in human disease. Thus, specifically reducing oligomeric tau at synapses may be a promising therapeutic strategy for Alzheimer's disease.

Antemortem network analysis of spreading pathology in autopsy-confirmed frontotemporal degeneration.

Despite well-articulated hypotheses of spreading pathology in animal models of neurodegenerative disease, the basis for spreading neurodegenerative pathology in humans has been difficult to ascertain. In this study, we used graph theoretic analyses of structural networks in antemortem, multimodal MRI from autopsy-confirmed cases to examine spreading pathology in sporadic frontotemporal lobar degeneration. We defined phases of progressive cortical atrophy on T1-weighted MRI using a published algorithm in autopsied frontotemporal lobar degeneration with tau inclusions or with transactional DNA binding protein of ∼43 kDa inclusions. We studied global and local indices of structural networks in each of these phases, focusing on the integrity of grey matter hubs and white matter edges projecting between hubs. We found that global network measures are compromised to an equal degree in patients with frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions compared to healthy controls. While measures of local network integrity were compromised in both frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, we discovered several important characteristics that distinguished between these groups. Hubs identified in controls were degraded in both patient groups, but degraded hubs were associated with the earliest phase of cortical atrophy (i.e. epicentres) only in frontotemporal lobar degeneration with tau inclusions. Degraded edges were significantly more plentiful in frontotemporal lobar degeneration with tau inclusions than in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, suggesting that the spread of tau pathology involves more significant white matter degeneration. Weakened edges were associated with degraded hubs in frontotemporal lobar degeneration with tau inclusions more than in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, particularly in the earlier phases of the disease, and phase-to-phase transitions in frontotemporal lobar degeneration with tau inclusions were characterized by weakened edges in earlier phases projecting to diseased hubs in subsequent phases of the disease. When we examined the spread of pathology from a region diseased in an earlier phase to physically adjacent regions in subsequent phases, we found greater evidence of disease spreading to adjacent regions in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions than in frontotemporal lobar degeneration with tau inclusions. We associated evidence of degraded grey matter hubs and weakened white matter edges with quantitative measures of digitized pathology from direct observations of patients' brain samples. We conclude from these observations that the spread of pathology from diseased regions to distant regions via weakened long-range edges may contribute to spreading disease in frontotemporal dementia-tau, while spread of pathology to physically adjacent regions via local neuronal connectivity may play a more prominent role in spreading disease in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions.

Development and Characterization of Mouse-Specific Anti-Tau Monoclonal Antibodies: Relevance for Analysis of Murine Tau in Cerebrospinal Fluid.

Clearance of tau seeds by immunization with tau antibodies is currently evaluated as therapeutic strategy to block the spreading of tau pathology in Alzheimer's disease and other tauopathies. Preclinical evaluation of passive immunotherapy is performed in different cellular culture systems and in wild-type and human tau transgenic mouse models. Depending on the preclinical model used, tau seeds or induced aggregates can either be of mouse, human or mixed origin. We aimed to develop human and mouse tau-specific antibodies to discriminate between the endogenous tau and the introduced form in preclinical models. Using hybridoma technology, we developed human and mouse tau-specific antibodies that were then used to develop several assays to specifically detect mouse tau. Four antibodies, mTau3, mTau5, mTau8, and mTau9, with a high degree of specificity for mouse tau were identified. Additionally, their potential application in highly sensitive immunoassays to measure tau in mouse brain homogenate and cerebrospinal fluid is illustrated, as well as their application for specific endogenous mouse tau aggregation detection. The antibodies reported here can be very important tools to better interpret the results obtained from different model systems as well as to study the role of endogenous tau in tau aggregation and pathology observed in the diverse mouse models available.

Apolipoprotein E Recognizes Alzheimer's Disease Associated 3‐O Sulfation of Heparan Sulfate

AbstractApolipoprotein E (ApoE)’s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell‐surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion‐like spread of tau pathology between cells. 3‐O‐sulfo (3‐O‐S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3‐O‐sulfated HS and 3‐O‐sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD‐linked ApoE4, and AD‐protective ApoE2 and ApoE3‐Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3‐O‐S. NMR titration localized ApoE/3‐O‐S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1‐a major 3‐O sulfotransferase‐reduced cell surface binding and uptake of ApoE. 3‐O‐S is thus recognized by both tau and ApoE, suggesting that the interplay between 3‐O‐sulfated HS, tau and ApoE isoforms may modulate AD risk.

Apolipoprotein E Recognizes Alzheimer's Disease Associated 3-O Sulfation of Heparan Sulfate.

Apolipoprotein E (ApoE)'s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell-surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion-like spread of tau pathology between cells. 3-O-sulfo (3-O-S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3-O-sulfated HS and 3-O-sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD-linked ApoE4, and AD-protective ApoE2 and ApoE3-Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3-O-S. NMR titration localized ApoE/3-O-S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1-a major 3-O sulfotransferase-reduced cell surface binding and uptake of ApoE. 3-O-S is thus recognized by both tau and ApoE, suggesting that the interplay between 3-O-sulfated HS, tau and ApoE isoforms may modulate AD risk.

Age-related and amyloid-beta-independent tau deposition and its downstream effects.

Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

Tau Transfer via Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System.

Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics, and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data indicate that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modifies their function.

Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model.

A key hallmark of Alzheimer's disease (AD) is the accumulation of hyperphosphorylated tau in neurofibrillary tangles. This occurs alongside neuroinflammation and neurodegeneration. Pathological tau propagates through the AD brain in a defined manner, which correlates with neuron and synapse loss and cognitive decline. One proposed mechanism of tau spread is through synaptically connected brain structures. Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset AD and is associated with increased tau burden. Whether the apolipoprotein E (APOE) genotype influences neurodegeneration via tau spread is currently unknown. Here, we demonstrate that virally expressed human tau (with the P301L mutation) injected into mouse entorhinal cortex at 5-6 months or 15-16 months of age spreads trans-synaptically to the hippocampus by 14 weeks post-injection. Injections of tau in mice expressing human APOE2, APOE3 or APOE4, as well as APOE knock-outs, showed that tau can spread trans-synaptically in all genotypes and that APOE genotype and age do not affect the spread of tau. These data suggest that APOE genotype is not directly linked to synaptic spread of tau in our model, but other mechanisms involving non-cell autonomous manners of tau spread are still possible.