Tau Spreading Research Articles

Domain-specific cognitive impairment is differentially affected by Alzheimer disease tau pathologic burden and spread

Abstract Tau pathology in Alzheimer disease (AD) is often evaluated in regions associated with episodic memory impairment. However, heterogeneous spreading patterns of tau are observed and correspond to impairment in different cognitive domains. We have previously developed a metric to quantify tau spread extent that is robustly sensitive to atypical spreading patterns. Here, we evaluate tau spread relative to domain-specific and general cognitive impairments during early stages of AD. 529 participants with baseline tau positron emission tomography (PET) and neuropsychological testing were separated into disease stage groups based on amyloid PET positivity and clinical status via CDR. General cognition was assessed using the Knight Preclinical Alzheimer Cognitive Composite (Knight PACC). Domain-specific composites were calculated for episodic memory, semantic memory, working memory, and attention/processing speed. Baseline tau burden, the average tau intensity across previously defined AD signature regions, and baseline tau spread extent, the proportion of the brain with elevated tau pathology, were quantified for each participant as Tau Index and Tau Spatial Spread respectively. Tau burden and tau spread were evaluated relative to baseline and longitudinal cognitive performance, as well as longitudinal clinical progression. Tau burden and tau spread extent both significantly correlate with cognitive impairment in symptomatic AD. Tau burden is most strongly correlated to episodic (r = -0.37, p = 0.02) and semantic (r = -0.36, p = 0.02) memory. In contrast, tau spread extent is most strongly correlated to the Knight PACC (r = -0.37, p = 0.01) and attention/processing speed (r = -0.44, p < 0.01), especially in preclinical AD (r = -0.27, p < 0.01). Tau burden captures more variance than tau spread extent in longitudinal change in the Knight PACC, episodic memory, semantic memory, attention/processing speed, and clinical progression. Tau burden strongly relates to baseline episodic and semantic memory, which may reflect that it is heavily weighted by entorhinal tau, a region previously linked to memory processing. In contrast, stronger associations between tau spread extent and baseline attention/processing speed could reflect the inclusion of additional brain regions, particularly the frontal lobe, which support a wider range of cognitive processing. Additionally, tau spread extent is generally more sensitive to baseline preclinical deficits, however tau burden better estimates future decline across all cognitive domains and clinical symptom onset. Together, these findings suggest complementary utility of evaluating both tau burden and tau spread extent in early AD progression.

Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.

The transmission of tau pathology has been proposed as one of the major mechanisms for the spatiotemporal spreading of tau pathology in neurodegenerative diseases. Over the last decade, studies have demonstrated that targeting total or pathological tau using tau antibodies can mitigate the development of tau pathology in tauopathy or Alzheimer's disease (AD) mouse models, and multiple tau immunotherapy agents have progressed to clinical trials. Tau antibodies are believed to inhibit the internalization of pathologic seeds and/or block seed elongation after seed internalization. To further address the mechanism of tau antibody inhibition of pathological spread, we conducted immunotherapy studies in mouse primary neurons and wild-type mice (females) seeded with AD patient-derived tau to induce the formation and spreading of tau pathology. Notably, we evaluated the effect of a mouse tau-specific antibody (mTau8) which does not interact with AD-tau seeds in these models. Our results show that mTau8 crosses the blood-brain barrier at levels similar to other antibodies and effectively decreases AD-tau-seeded tau pathology in vitro and in vivo. Importantly, our data suggest that mTau8 binds to endogenous intraneuronal mouse tau, thereby inhibiting the elongation of internalized tau seeds. These findings provide valuable insights into the possible mechanism underlying antibody-based therapies for treating tauopathies.Significance Statement The transmission of tau pathology plays key role in the pathoclinical progression of tauopathy. Studies have shown that tau antibody treatment can mitigate tau pathology in transgenic and spreading models of tauopathy. To explore the mechanisms involved in this procedure, we conducted immunotherapy studies on human tau seeds induced tau spreading models using a mouse tau-specific antibody (mTau8), which does not interact with human-tau seeds. Our findings in the study enhance our understanding of antibody-based therapies for tauopathies.

Gastrointestinal tract cleavage of α-synuclein by asparaginyl endopeptidase leads to Parkinson’s disease

Pathologic α-synuclein (α-syn) aggregates from the gastrointestinal (GI) tract may contribute to Parkinson's disease (PD). Xiang etal.1 report in Neuron that enteric nervous system-specific expression of asparaginyl endopeptidase (AEP)-truncated α-syn and tau spreads to the brain, synergistically causing PD-related neurodegeneration and neurobehavioral deficits.

Morphometry of medial temporal lobe subregions using high-resolution T2-weighted MRI in ADNI3: Why, how, and what's next?

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration.

A Drosophila model for mechanistic investigation of tau protein spread.

Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau (encoded by MAPT) in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We found age-dependent spread of tau into the brain, represented by detection of tau, but not of GFP. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin (encoded by shi) or knockdown of glycogen synthase kinase-3β (GSK-3β, encoded by sgg). Further work revealed that dynamin promoted tau uptake in recipient tissues, whereas GSK-3β appeared to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau-trafficking components involved in the pathogenesis of neurodegenerative diseases.

HSV-1 infection induces phosphorylated tau propagation among neurons via extracellular vesicles.

Extracellular vesicles (EV), key players in cell-to-cell communication, may contribute to disease propagation in several neurodegenerative diseases, including Alzheimer's disease (AD), by favoring the dissemination of neurotoxic proteins within the brain. Interestingly, growing evidence supports the role of herpes simplex virus type 1 (HSV-1) infection in the pathogenesis of AD. Here, we investigated whether HSV-1 infection could promote the spread of phosphorylated tau (ptau) among neurons via EV. We analyzed the ptau species that were secreted via EV following HSV-1 infection in neuroblastoma cells and primary neurons, focusing particularly on T205, T181, and T217, the phosphorylation sites mainly associated with AD. Moreover, by overexpressing human tau tagged with GFP (htauGFP), we found that recipient tau knockout (KO) neurons uptook EV that are loaded with HSV-1-induced phtauGFP. Finally, we exploited an in vivo model of acute infection and assessed that cerebral HSV-1 infection promotes the release of ptau via EV in the brain of infected mice. Overall, our data suggest that, following HSV-1 infection, EV play a role in tau spreading within the brain, thus contributing to neurodegeneration.IMPORTANCEHerpes simplex virus type 1 (HSV-1) infection that reaches the brain has been repeatedly linked with the appearance of the pathognomonic markers of Alzheimer's disease (AD), including accumulation of amyloid beta and hyperphosphorylated tau proteins, and cognitive deficits. AD is a multifactorial neurodegenerative disease representing the most common form of dementia in the elderly, and no cure is currently available, thus prompting additional investigation on potential risk factors and pathological mechanisms. Here, we demonstrate that the virus exploits the extracellular vesicles (EV) to disseminate phosphorylated tau (ptau) among brain cells. Importantly, we provide evidence that the HSV-1-induced EV-bearing ptau can be undertaken by recipient neurons, thus likely contributing to misfolding and aggregation of native tau, as reported for other AD models. Hence, our data highlight a novel mechanism exploited by HSV-1 to propagate tau-related damage in the brain.

Chronic Neuronal Hyperexcitation Exacerbates Tau Propagation in a Mouse Model of Tauopathy.

The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer's disease (AD) and other tauopathies. Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited. In this study, we investigated how tau propagation from the entorhinal cortex to the hippocampus, the neuronal circuit most susceptible to tau pathology in AD, is affected by the selective stimulation of neuronal activity along this circuit. Using a mouse model of seed-induced propagation combined with optogenetics, we found that the chronic stimulation of this neuronal connection over a 4-week period resulted in a significant increase in insoluble tau accumulation in both the entorhinal cortex and hippocampus. Importantly, the ratio of tau accumulation in the hippocampus relative to that in the entorhinal cortex, serving as an indicator of transcellular spreading, was significantly higher in mice subjected to chronic stimulation. These results support the notion that abnormal neuronal activity promotes tau propagation, thereby implicating it in the progression of tauopathy.

Increased between-network connectivity: A risk factor for tau elevation and disease progression

One of the pathologic hallmarks of Alzheimer’s disease (AD) is neurofibrillary tau tangles. Despite our knowledge that tau typically initiates in the medial temporal lobe (MTL), the mechanisms driving tau to spread beyond MTL remain unclear. Emerging evidence reveals distinct patterns of functional connectivity change during aging and preclinical AD: while connectivity within-network decreases, connectivity between-network increases. Building upon increased between-network connectivity, our study hypothesizes that this increase may play a critical role in facilitating tau spread in early stages. We conducted a longitudinal study over two to three years intervals on a cohort of 46 healthy elderly participants (mean age 64.23 ± 3.15 years, 26 females). Subjects were examined clinically and utilizing advanced imaging techniques that included resting-state functional MRI (rs-fMRI), structural magnetic resonance imaging (MRI), and a second-generation positron emission tomography (PET) tau tracer, 18F-MK6240. Through unsupervised agglomerative clustering and increase in between-network connectivity, we successfully identified individuals at increased risk of future tau elevation and AD progression. Our analysis revealed that individuals with increased between-network connectivity are more likely to experience more future tau deposition, entorhinal cortex thinning, and lower selective reminding test (SRT) delayed scores. Additionally, in the limbic network, we found a strong association between tau progression and increased between-network connectivity, which was mainly driven by beta-amyloid (Aβ) positive participants. These findings provide evidence for the hypothesis that an increase in between-network connectivity predicts future tau deposition and AD progression, also enhancing our understanding of AD pathogenesis in the preclinical stages.

Variable and interactive effects of Sex, APOE and TREM2 on the deposition of tau in entorhinal and neocortical regions.

The canonical AD pathological cascade posits that the accumulation of amyloid beta ( ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a sample of over 1300 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and homozygotes are more susceptible to the effects of on the primary accumulation of tau, with greater EC tau for a given level of . Furthermore, we observed for individuals who have rare risk variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and/or homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression, and have implications for determining personalised treatment with drugs targeting and tau.

Exploring the link between dystrophic microglia and the spread of Alzheimer's neuropathology.

Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease (AD) progression, but details of microglia's disease-driving influence are poorly understood. Microglial cells can be parsed into subtypes based on their histologic appearance. One microglia subtype, termed dystrophic microglia, is characterised structurally by fragmented processes and cytoplasmic decay, and their presence has been associated with ageing and neurodegeneration. Recent studies suggest that the interaction between tau proteins and amyloid-β might induce dystrophic changes in microglia, potentially linking amyloid-β and tau pathologies to their effects on these microglia. We developed a study of human brains to test the hypothesis that dystrophic microglia are involved in AD progression. We speculated that if their presence is unique to AD neuropathologic change (ADNC), they would be substantially more common in ADNC than in neurodegenerative diseases characterised by other proteinopathies, e.g., α-synuclein or TDP-43 pathology. Our analyses used histologically stained sections from five human brain regions of 64 individuals across six disease states, from healthy controls to advanced AD stages, including comparative conditions such as Lewy Body Disease (LBD) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Using stereological sampling and digital pathology, we assessed ramified, hypertrophic, and dystrophic microglia populations. We found a significant increase in dystrophic microglia in areas early affected by ADNC, suggesting a disease-specific role in neuropathology. Mediation analysis and structural equation modelling suggest dystrophic microglia may impact the regional spread of ADNC. In the mediation model, tau was found to be the initiating factor leading to the development of dystrophic microglia, which then was associated with the spread of amyloid-β and tau. These results suggest that a loss of microglia's protective role could contribute to the spread of ADNC and indicate that further research into preserving microglial function may be warranted.

TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice

In Alzheimer’s disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer’s disease.

Temporal progression of tau pathology and neuroinflammation in a rhesus monkey model of Alzheimer's disease.

The understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic. To examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection. Using quantitative microscopy targeting markers for neurodegeneration and neuroinflammation, as well as fluid and imaging biomarkers, we detailed the progression of misfolded tau spreading and the consequential inflammatory response induced by glial cells. By combining the analysis of several in vivo biomarkers with extensive brain microscopy analysis, we described the initial steps of misfolded tau spreading and neuroinflammation in a monkey model highly translatable to AD patients. Dual tau mutation delivery in the entorhinal cortex induces progressive tau pathology in rhesus macaques. Exogenous human 4R-tau coaptates monkey 3R-tau during transneuronal spread, in a prion-like manner. Neuroinflammatory response is coordinated by microglia and astrocytes in response to tau pathology, with microglia targeting early tau pathology, while astrocytes engaged later in the progression, coincident with neuronal death. Monthly collection of CSF and plasma revealed a profile of changes in several AD core biomarkers, reflective of neurodegeneration and neuroinflammation as early as 1 month after injection.

Neuroinflammation Parallels 18F-PI-2620 Positron Emission Tomography Patterns in Primary 4-Repeat Tauopathies.

Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4-repeat (4R) tauopathies and its role in accelerating disease progression. We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading. We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3-T resting-state functional magnetic resonance imaging template derived from age-matched healthy elderly controls. In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO-PET across brain regions that are functionally connected to each other (β = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient-specific tau epicenters (β = -0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F-PI-2620 PET. Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease-modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The autophagy adaptor TRIAD3A promotes tau fibrillation by nested phase separation.

Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report a RING-in-between-RING-type E3 ligase, TRIAD3A, that functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age-progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyses mixed K11/K63 polyubiquitin chains and self-assembles into liquid-liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and, via LC3 interacting regions, targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies show that TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and a disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis and increases pathological tau spreading. In human Alzheimer disease brain, TRIAD3A co-localizes with tau amyloid in multiple histological forms, suggesting a role in tau proteostasis. TRIAD3A is an autophagic adaptor that utilizes E3 ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases.

Drosophila appear resistant to trans-synaptic tau propagation.

Alzheimer's disease is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of Alzheimer's disease is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models, and indirect evidence for tau spread via synapses has been observed in human Alzheimer's disease. Halting tau propagation is a promising therapeutic target for Alzheimer's disease; thus, a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau in Drosophila melanogaster. Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing four different human tau constructs in two distinct neuronal populations reveals a robust resistance in Drosophila to the trans-synaptic spread of human tau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global human tau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish that Drosophila expressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed in Drosophila may serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies.

Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline.

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (β=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β=0.006, p < 0.01) and global tau SUVR (β=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.

Disruption in functional networks mediated tau spreading in Alzheimer's disease.

Alzheimer's disease may be conceptualized as a 'disconnection syndrome', characterized by the breakdown of neural connectivity within the brain as a result of amyloid-beta plaques, tau neurofibrillary tangles and other factors leading to progressive degeneration and shrinkage of neurons, along with synaptic dysfunction. It has been suggested that misfolded tau proteins spread through functional connections (known as 'prion-like' properties of tau). However, the local effect of tau spreading on the synaptic function and communication between regions is not well understood. I aimed to investigate how the spreading of tau aggregates through connections can locally influence functional connectivity. In total, the imaging data of 211 participants including 117 amyloid-beta-negative non-demented and 94 amyloid-beta-positive non-demented participants were recruited from the Alzheimer's Disease Neuroimaging Initiative. Furthermore, normative resting-state functional MRI connectomes were used to model tau spreading through functional connections, and functional MRI of the included participants was used to determine the effect of tau spreading on functional connectivity. I found that lower functional connectivity to tau epicentres is associated with tau spreading through functional connections in both amyloid-beta-negative and amyloid-beta-positive participants. Also, amyloid-beta-PET in tau epicentres mediated the association of tau spreading and functional connectivity to epicentres suggesting a partial mediating effect of amyloid-beta deposition in tau epicentres on the local effect of tau spreading on functional connectivity. My findings provide strong support for the notion that tau spreading through connection is locally associated with disrupted functional connectivity between tau epicentre and non-epicentre regions independent of amyloid-beta pathology. Also, I defined several groups based on the relationship between tau spreading and functional disconnection, which provides quantitative assessment to investigate susceptibility or resilience to functional disconnection related to tau spreading. I showed that amyloid-beta, other copathologies and the apolipoprotein E epsilon 4 allele can be a leading factor towards vulnerability to tau relative functional disconnection.

Chromogranin A (CgA) Deficiency Attenuates Tauopathy by Altering Epinephrine-Alpha-Adrenergic Receptor Signaling.

Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimer's disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.

Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer’s disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.

Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus

Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form of paired helical filaments is a major hallmark of Alzheimer’s disease. Subcellular localization of ptau at various stages of disease progression is likely to be informative of the cellular mechanisms involving its spread. Here, we found that the density of ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn) consistently being the most affected. In the ADn, ptau-positive elements were present already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites, and in a specialized type of presynaptic terminal that expresses vesicular glutamate transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing terminals displayed signs of degeneration, including endosomal/lysosomal organelles. In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the involvement of a specific cell population in ADn at the onset of the disease. The presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses about the transsynaptic spread of tau selectively affecting specialized axonal pathways.