Distribution Of Tau Research Articles

Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology.

Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort. Clinical variants were diagnosed antemortem, and brain tissue was collected post-mortem. Typical AD (n= 10), behavioural/dysexecutive AD (n= 6), posterior cortical atrophy (PCA) AD (n= 3), and controls (n= 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid-β, CD68, MHC-II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology. Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid-β was neocortical-dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE-NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC-II were hippocampal-dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC-II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants. Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.

A machine learning-based prediction of tau load and distribution in Alzheimer's disease using plasma, MRI and clinical variables.

Tau positron emission tomography (PET) is a reliable neuroimaging technique for assessing regional load of tau pathology in the brain, commonly used in Alzheimer's disease (AD) research and clinical trials. However, its routine clinical use is limited by cost and accessibility barriers. Here we explore using machine learning (ML) models to predict clinically useful tau-PET composites from low-cost and non-invasive features, e.g., basic clinical variables, plasma biomarkers, and structural magnetic resonance imaging (MRI). Results demonstrated that models including plasma biomarkers yielded the most accurate predictions of tau-PET burden (best model: R-squared=0.66-0.68), with especially high contribution from plasma P-tau217. In contrast, MRI variables stood out as best predictors (best model: R-squared=0.28-0.42) of asymmetric tau load between the two hemispheres (an example of clinically relevant spatial information). The models showed high generalizability to external test cohorts with data collected at multiple sites. Based on these results, we also propose a proof-of-concept two-step classification workflow, demonstrating how the ML models can be translated to a clinical setting. This study uncovers current potential in predicting tau-PET information from scalable cost-effective variables, which could improve diagnosis and prognosis of AD.

Quantifying Treatments as Usual and with Technologies in Neurorehabilitation of Individuals with Spinal Cord Injury.

Several technologies have been introduced into neurorehabilitation programs to enhance traditional treatment of individuals with Spinal Cord Injury (SCI). Their effectiveness has been widely investigated, but their adoption has not been properly quantified. The aim of this study is to assess the distribution of conventional (Treatment As Usual-TAU) and technology-aided (Treatment With Technologies-TWT) treatments conveniently grouped based on different therapeutic goals in a selected SCI unit. Data from 104 individuals collected in 29 months were collected in a custom database and categorized according to both the conventional American Impairment Scale classification and a newly developed Multifactor (MF) clustering approach that considers additional sources of information (the lesion level, the level of independence in the activities of daily living, and the hospitalization duration). Results indicated an average technology adoption of about 30%. Moreover, the MF clusters were less overlapped, and the differences in TWT adoption were more pronounced than in AIS-based clustering. MF clustering was capable of grouping individuals based both on neurological features and functional abilities. In particular, individuals with motor complete injuries were grouped together, whereas individuals with sensorimotor incomplete SCI were collected separately based on the lesion level. As regards TWT adoption, we found that in the case of motor complete SCI, TWT for muscle tone control and modulation was mainly selected (about 90% of TWT), while the other types of TWT were seldom adopted. Even for individuals with incomplete SCI, the most frequent rehabilitation goal was muscle tone modulation (about 75% of TWT), regardless of the AIS level, and technologies to improve walking ability (about 12% of TWT) and balance control (about 10% of TWT) were mainly used for individuals with thoracic or lumbar lesions. Analyzing TAU distribution, we found that the highest adoption of muscle tone modulation strategies was reported in the case of individuals with motor complete SCI (about 42% of TAU), that is, in cases when almost no gait training was pursued (about 1% of TAU). In the case of cervical motor incomplete SCI, compared to thoracic and lumbar incomplete SCI, there was a greater focus on muscle tone control and force recruitment in addition to walking training (38% and 14% of TAU, respectively) than on balance training. Overall, the MF clustering provided more insights than the traditional AIS-based classification, highlighting differences in TWT adoption. These findings suggest that a wider overview that considers both neurological and functional characteristics of individuals after SCI based on a multifactor analysis could enhance the personalization of neurorehabilitation strategies.

Correlation between clinical and neuropathological subtypes of PSP: Do clinical symptoms reflect tau distribution?

Correlation between clinical and neuropathological subtypes of PSP: Do clinical symptoms reflect tau distribution?

Flortaucipir PET uncovers relationships between tau and amyloid-β in primary age-related tauopathy and Alzheimer's disease.

[18F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer's disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-β. It is also unclear whether flortaucipir can detect tau in definite primary age-related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [18F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-β PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-β phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-β phase. Flortaucipir uptake linearly increased with the amyloid-β phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer's disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-β phase, and were useful for distinguishing different ADNC scores and PART.

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.

SARS-CoV-2 Nucleocapsid Protein Induces Tau Pathological Changes That Can Be Counteracted by SUMO2.

Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer's pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.

Tau follows principal axes of functional and structural brain organization in Alzheimer’s disease

Alzheimer’s disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns (“gradient contraction”) are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.

Differential accumulation of human β-amyloid and tau from enriched extracts in neuronal and endothelial cells

While Aβ and Tau cellular distribution has been largely studied, the comparative internalization and subcellular accumulation of Tau and Aβ isolated from human brain extracts in endothelial and neuronal cells has not yet been unveiled. We have previously demonstrated that controlled enrichment of Aβ from human brain extracts constitutes a valuable tool to monitor cellular internalization in vitro and in vivo. Herein, we establish an alternative method to strongly enrich Aβ and Tau aggregates from human AD brains, which has allowed us to study and compare the cellular internalization, distribution and toxicity of both proteins within brain barrier endothelial (bEnd.3) and neuronal (Neuro2A) cells. Our findings demonstrate the suitability of human enriched brain extracts to monitor the intracellular distribution of human Aβ and Tau, which, once internalized, show dissimilar sorting to different organelles within the cell and differential toxicity, exhibiting higher toxic effects on neuronal cells than on endothelial cells. While tau is strongly concentrated preferentially in mitochondria, Aβ is distributed predominantly within the endolysosomal system in endothelial cells, whereas the endoplasmic reticulum was its preferential location in neurons. Altogether, our findings display a picture of the interactions that human Aβ and Tau might establish in these cells.

Histologic tau lesions and magnetic resonance imaging biomarkers differ across two progressive supranuclear palsy variants.

Progressive supranuclear palsy is a neurodegenerative disease characterized by the deposition of four-repeat tau in neuronal and glial lesions in the brainstem, cerebellar, subcortical and cortical brain regions. There are varying clinical presentations of progressive supranuclear palsy with different neuroimaging signatures, presumed to be due to different topographical distributions and burden of tau. The classic Richardson syndrome presentation is considered a subcortical variant, whilst progressive supranuclear palsy with predominant speech and language impairment is considered a cortical variant, although the pathological underpinnings of these variants are unclear. In this case-control study, we aimed to determine whether patterns of regional tau pathology differed between these variants and whether tau burden correlated with neuroimaging. Thirty-three neuropathologically confirmed progressive supranuclear palsy patients with either the Richardson syndrome (n = 17) or speech/language (n = 16) variant and ante-mortem magnetic resonance imaging were included. Tau lesion burden was semi-quantitatively graded in cerebellar, brainstem, subcortical and cortical regions and combined to form neuronal and glial tau scores. Regional magnetic resonance imaging volumes were converted to Z-scores using 33 age- and sex-matched controls. Diffusion tensor imaging metrics, including fractional anisotropy and mean diffusivity, were calculated. Tau burden and neuroimaging metrics were compared between groups and correlated using linear regression models. Neuronal and glial tau burden were higher in motor and superior frontal cortices in the speech/language variant. In the subcortical and brainstem regions, only the glial tau burden differed, with a higher burden in globus pallidus, subthalamic nucleus, substantia nigra and red nucleus in Richardson's syndrome. No differences were observed in the cerebellar dentate and striatum. Greater volume loss was observed in the motor cortex in the speech/language variant and in the subthalamic nucleus, red nucleus and midbrain in Richardson's syndrome. Fractional anisotropy was lower in the midbrain and superior cerebellar peduncle in Richardson's syndrome. Mean diffusivity was greater in the superior frontal cortex in the speech/language variant and midbrain in Richardson's syndrome. Neuronal tau burden showed associations with volume loss, lower fractional anisotropy and higher mean diffusivity in the superior frontal cortex, although these findings did not survive correction for multiple comparisons. Results suggest that a shift in the distribution of tau, particularly neuronal tau, within the progressive supranuclear palsy network of regions is driving different clinical presentations in progressive supranuclear palsy. The possibility of different disease epicentres in these clinical variants has potential implications for the use of imaging biomarkers in progressive supranuclear palsy.

Inner Back Cover Image

ON THE INNER BACK COVER: Distribution of tau in the adult rat hippocampus (CA3 region shown). The tissue section was dephosphorylated and then stained with Tau1 antibody (white), MAP2 (red) and DAPI (blue). Tau is normally found at abundant levels within the soma, dendrites, axons and some nuclei of neurons (pink indicates colocalization between Tau1 and MAP2 signal).Credit: Nicholas Kanaan, PhD, Michigan State Universityimage

Optimized Calcium-Phosphate-Based Co-transfection of Tau and tdTomato into Human iPSC-Derived Neurons for the Study of Intracellular Distribution of Wild-type and Mutant Human Tau.

The study of Tau protein in disease-relevant neuronal cells in culture requires efficient delivery systems for transfection of exogenous Tau and also modulators and interactors of Tau. Transfection of cultivated cells using calcium phosphate precipitation is a simple and cost-effective approach, also for difficult-to-transfect and sensitive cells such as primary neurons. Because of its low cell toxicity and ease of use, the Ca2+-phosphate transfection method is one of the most widely used gene transfer procedures in neuroscience. However, Ca2+-phosphate transfection efficacy in neurons is poor, often in the range of 1-5%, limiting its use in functional investigations. Here, we outline our improved Ca2+-phosphate transfection methodology for human iPSC-derived neurons that yields a reasonable efficiency (20-30% for bright volume markers) without apparent effects on cell health. We have used it to introduce wild-type and mutant human Tau with and without co-transfection of a volume marker (used here: tdTomato). In sum, our procedure can deliver neuronal genes (e.g., MAPT) using typical eukaryotic expression vectors (e.g., using CMV promoter) and is optimized for transfection of human iPSC-derived neurons.

Tracking Tau in Neurons: How to Transfect and Track Exogenous Tau in Primary Neurons.

Primary murine neurons have proved to be an essential tool for the general investigation of neuronal polarity, polarized Tau distribution, and Tau-based neuronal dysfunction in disease paradigms. However, mature primary neurons are notoriously difficult to transfect with non-viral approaches and are very sensitive to cytoskeletal manipulation and imaging. Furthermore, standard non-viral transfection techniques require the use of a supportive glial monolayer or high-density cultures, both of which interfere with microscopy. Here we provide a simple non-viral liposome-based transfection method that enables transfection of Tau in low levels comparable to endogenous Tau. This allows the investigation of, for example, distribution and trafficking of Tau, without affecting other cytoskeleton-based parameters such as microtubule density or microtubule-based transport. Using this protocol, we achieve a profound transfection efficiency but avoid high overexpression rates. Importantly, this transfection method can be applied to neurons at different ages and is also suitable for very old cultures (up to 18days in vitro). In addition, the protocol can be used in cultures without glial support and at suitable cell densities for microscopy-based single cell analysis. In sum, this protocol has proven a reliable tool suitable for most microscopy-based approaches in our laboratory.

Super-Resolution Imaging of Tau Proteins in Isolated and Immobilized Brain Synaptosomes.

Tau protein has important physiological functions at both presynaptic and postsynaptic terminals. Pathological tau species are also associated with synaptic dysfunctions in several neurodegenerative disorders, especially Alzheimer's disease. To understand tau distribution inside synaptic compartments, super-resolution imaging is required. Here, we describe a facile protocol to immobilize and image brain synaptosomes without aggregation artefacts, by substituting the standard fixative paraformaldehyde with ethylene glycol bis(succinimidyl succinate) (EGS). Super-resolution imaging of tau proteins is achieved through three-color direct stochastic optical reconstruction microscopy (dSTORM). Tau protein is found to colocalize with synaptic vesicles as well as postsynaptic densities.

Tau accumulation and its spatial progression across the Alzheimer's disease spectrum.

The accumulation of tau abnormality in sporadic Alzheimer's disease is believed typically to follow neuropathologically defined Braak staging. Recent in-vivo PET evidence challenges this belief, however, as accumulation patterns for tau appear heterogeneous among individuals with varying clinical expressions of Alzheimer's disease. We, therefore, sought a better understanding of the spatial distribution of tau in the preclinical and clinical phases of sporadic Alzheimer's disease and its association with cognitive decline. Longitudinal tau-PET data (1370 scans) from 832 participants (463 cognitively unimpaired, 277 with mild cognitive impairment and 92 with Alzheimer's disease dementia) were obtained from the Alzheimer's Disease Neuroimaging Initiative. Among these, we defined thresholds of abnormal tau deposition in 70 brain regions from the Desikan atlas, and for each group of regions characteristic of Braak staging. We summed each scan's number of regions with abnormal tau deposition to form a spatial extent index. We then examined patterns of tau pathology cross-sectionally and longitudinally and assessed their heterogeneity. Finally, we compared our spatial extent index of tau uptake with a temporal meta-region of interest-a commonly used proxy of tau burden-assessing their association with cognitive scores and clinical progression. More than 80% of amyloid-beta positive participants across diagnostic groups followed typical Braak staging, both cross-sectionally and longitudinally. Within each Braak stage, however, the pattern of abnormality demonstrated significant heterogeneity such that the overlap of abnormal regions across participants averaged less than 50%, particularly in persons with mild cognitive impairment. Accumulation of tau progressed more rapidly among cognitively unimpaired and participants with mild cognitive impairment (1.2 newly abnormal regions per year) compared to participants with Alzheimer's disease dementia (less than 1 newly abnormal region per year). Comparing the association of tau pathology and cognitive performance our spatial extent index was superior to the temporal meta-region of interest for identifying associations with memory in cognitively unimpaired individuals and explained more variance for measures of executive function in patients with mild cognitive impairments and Alzheimer's disease dementia. Thus, while participants broadly followed Braak stages, significant individual regional heterogeneity of tau binding was observed at each clinical stage. Progression of the spatial extent of tau pathology appears to be fastest in cognitively unimpaired and persons with mild cognitive impairment. Exploring the spatial distribution of tau deposits throughout the entire brain may uncover further pathological variations and their correlation with cognitive impairments.

Tau here, tau there, tau almost everywhere: Clarifying the distribution of tau in the adult CNS.

The microtubule-associated protein tau has gained significant attention over the last several decades primarily due to its apparent role in the pathogenesis of several diseases, most notably Alzheimer's disease. While the field has focused largely on tau's potential contributions to disease mechanisms, comparably less work has focused on normal tau physiology. Moreover, as the field has grown, some misconceptions and dogmas regarding normal tau physiology have become engrained in the traditional narrative. Here, one of the most common misconceptions regarding tau, namely its normal cellular/subcellular distribution in the CNS, is discussed. The literature describing the presence of tau in neuronal somata, dendrites, axons and synapses, as well as in glial cells is described. The origins for the erroneous description of tau as an "axon-specific," "axon-enriched" and/or "neuron-specific" protein are discussed as well. The goal of this work is to help address these specific dogmatic misconceptions and provide a concise description of tau's normal cellular/subcellular localization in the adult CNS. This information can help refine our collective understanding of- and hypotheses about tau biology and pathobiology.

Gray to White Matter Signal Ratio as a novel biomarker of neurodegeneration in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is characterized neuropathologically by ß‐amyloid (Aß) plaques, hyperphosphorylated tau neurofibrillary tangles, and neurodegeneration which leads to a phenotypically heterogeneous cognitive‐behavioral dementia syndrome. Our understanding of how these neuropathological and neurodegeneration biomarkers relate to each other is still evolving. A relatively new approach to measuring structural brain change, gray matter to white matter signal intensity ratio (GWR), quantifies the signal contrast between these tissue compartments, and has emerged as a promising marker of AD‐related neurodegeneration. We sought to validate GWR as a novel MRI biomarker of neurodegeneration.MethodTwenty‐nine amyloid‐, tau‐, and neurodegeneration positive patients with atypical syndromes of AD (16 Posterior Cortical Atrophy, 10 logopenic variant of Primary Progressive Aphasia, and 3 Amnestic Dysexecutive phenotype) and 24 amyloid‐negative control participants underwent structural MRI, 11C‐Pittsburgh Compound B (PiB) PET, and 18F‐flortaucipir (FTP) PET scans. Whole‐cortex vertex‐wise general linear models (GLM) were created to identify areas of the cerebral cortex where AD patients showed abnormal signal in each modality, and Pearson’s correlation coefficients were computed to examine the strength of bivariate associations between each pair of modalities at the group level. We then constructed linear mixed‐effects models to test the relative contribution of each non‐FTP modality to explaining the variance in regional FTP uptake.ResultWe found that GWR was associated with cortical thickness, tau PET, and amyloid PET, with GWR showing a larger magnitude of abnormality than cortical thickness. We also found that combining GWR, cortical thickness, and amyloid PET better explained observed tau PET signal than using these modalities alone, suggesting that the three imaging biomarkers contribute independently and synergistically to explaining the variance in the distribution of tau pathology.ConclusionWe conclude that GWR is a uniquely sensitive in vivo marker of neurodegenerative change that reflects pathological mechanisms which may occur prior to cortical atrophy. By using all of these imaging biomarkers of AD together, we may be better able to capture, and possibly predict, AD neuropathologic changes in vivo, which we hope will ultimately contribute to better endpoints to evaluate the efficacy of therapeutic interventions as we move toward an era of disease‐modifying treatments for this devastating disease.

SARS‐CoV2 Nucleocapsid Protein induces Tau pathological changes in the mouse hippocampus

AbstractBackgroundNeurologic manifestations are emerging as an immediate consequence of SARS‐CoV2 infection, the etiologic agent of COVID19. Although little is known about the long‐term consequences of SARS‐CoV2 infection, there is the possibility that infection may trigger long‐term neurological effects. Exposure to pathogens in fact triggers inflammation in the brain and exacerbates Tau pathological changes in animal models of Alzheimer disease. Reports of the presence of SARS‐CoV2 in the brains of subjects with COVID19 are emerging and a study in brain organoids revealed that SARS‐CoV2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to recruitment of Tau into stress granules (SG) operated by the Nucleocapsid protein (NP) of SARS‐CoV2.MethodTo address whether exposure to SARS‐CoV2 may predispose to develop dementia, we investigated whether NP interacts with Tau and induces hyperphosphorylation and aggregation of Tau in human iPSC cells and hippocampal neurons in vivo. We tested whether NP interacts with Tau by co‐immunoprecipitation experiments. Mechanistically, we tested whether posttranslational modification of NP and Tau by SUMO2 modulates their distribution in SG and their pathological interaction. We expressed NP for 2 months, with or without SUMO2, in the hippocampus of 6 months old wild type and JNPL3 mice, before performing Y‐maze. After behavioral assessment, the mice were sacrificed and brains were isolated to perform biochemical and immunofluorescence analyses.ResultWe found that NP and Tau co‐localize and physically interact in human cells. We also found that NP induces hyperphosphorylation of Tau and reduces the amount of synaptic proteins in neurons. This is also paralleled by a reduction in the cognitive abilities of mice infected with NP in their hippocampus. Finally we found that modulation of SUMOylation dramatically affects SG induced by NP in cells, Tau hyperphoshorylation, as well as cognitive performance in mice infected with NP.ConclusionOur data demonstrate that NP induces pathological changes in cells and animals expressing wild type Tau, and aggravates the pathology in neurons expressing mutant forms of Tau, both in vitro and in vivo. Moreover we demonstrate that SUMO2 conjugation ameliorates NP‐induced Tau pathology.

Mapping the effects of functional and structural network reorganization on the tau‐cognition relationship in Alzheimer’s disease

AbstractBackgroundTau pathology can spread through connectivity‐based networks, with certain regions (or epicenters) accumulating more tau than others. Such spatial vulnerabilities may be due to their unique apical position in the cortical hierarchy, which can be elucidated through ‘gradients of connectivity’ (Margulies 2016 PNAS). Prior work showed that the primary gradient of functional connectivity unveils a uni‐to‐transmodal topography of the healthy neocortex which highly correlates with a cognitive gradient of perception‐to‐abstraction. Here, we hypothesized that the gradients of functional/structural connectivity interact with tau to affect cognitive functions in Alzheimer’s disease (AD).MethodWe included 213 participants from TRIAD (103 CN Aß‐, 103 CN Aß+, and 75 CI Aß+) with diffusion‐weighted MRI, resting‐state functional MRI, 18F‐MK6240 tau‐PET, and an extensive cognitive battery. We performed non‐linear dimensionality reduction on the individual functional and structural connectomes, and extracted the first components (‘gradients’) ‐explaining most variance (G1FC and G1SC). First, we compared G1FC_or_SC between diagnostic groups. Second, we investigated the interaction effect of G1FC_or_SC*tauSUVR on cognition (across 9 cognitive domains). Last, we investigated whether the tau‐cognition relationship changed in a topography‐specific manner along the cortical hierarchy, within (equally‐sized) gradient‐derived meta‐ROIs along G1FC_or_SC. Results were compared to Braak‐derived regional associations. Analyses were adjusted for age, sex, APOE, education, and multiple comparisons.ResultWe observed reduced segregation of functional networks in AD compared to controls, with unimodal (lower‐order cognitive) and transmodal (higher‐order cognitive) regions moving closer on G1FC. This may indicate loss of network specialization in AD. Participants who had both higher tau and G1FC alterations had more cognitive impairment (Fig.1A; shown for MMSE/language). This interaction‐effect was less pronounced with G1SC (Fig.1B). Last, tau correlated with cognition in a topography‐specific progressive manner (i.e., along the transmodal‐unimodal G1FC axis and anterior‐posterior G1SC axis) (Fig.1C). Notably, tau correlated with delayed memory progressively along the posterior‐anterior G1SC axis (R2 = 0.93 in all and R2 = 0.95 in A+) and BraakI‐VI axis (R2 = 0.77 in all and R2 = 0.28 in A+).ConclusionOur work supports the contribution of connectome‐driven tau distribution on cognitive impairment in AD. Connectome gradients may provide a spatial framework to study tau spreading along the major axes of brain organization underlying specific cognitive domains.

Brain vasculature influences local tau accumulation in the human inferior temporal gyrus

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that involves the accumulation of pathological tau protein. While the mechanisms behind tau accumulation are not well understood, they are pivotal to understanding the pathogenesis of AD. Because protein clearance in the brain is mediated in part by vasculature, we hypothesize that vasculature may direct the accumulation and distribution of tau pathology. In this study, we analyzed the spatial relationship between tau distribution and vasculature to elucidate vasculature’s role in tau clearance.MethodPost‐mortem human tissue samples (∼1 cm3) from the inferior temporal gyrus of 6 AD and 6 control donors were sliced at thicknesses of 500 µm to 1 mm. Tissue slices were prepared with tissue clearing. Cleared samples were stained with antibodies for tau (AT8), vasculature (GLUT1), nuclei (DAPI), and neurons (HUD). Images were collected using confocal fluorescence microscopy. A virtual reality tracing method was developed to segment individual blood vessels across large tissue volumes and 12‐21 individual vessels were isolated in each sample. Novel MATLAB scripts were developed to calculate the intensity of tau as a function of distance from the blood vessels’ surfaces.ResultIn AD samples, tau intensity varied along the length of the blood vessel and with distance from the blood vessel surface. Regions with high tau accumulation on the blood vessel surface exhibited elevated tau accumulation in the surrounding tissue. In regions with low tau accumulation on the blood vessel surface, tau intensity was observed to decrease near the vessel. The influence of blood vessels on tau intensity dissipated as distance from the vessel surface increased, where tau intensity approached the bulk value (average tau intensity across the entire image). Compared to AD samples, control tissue showed little AT8+ tau labeling and the relationship between tau and distance from blood vessels was not apparent.ConclusionThese results indicate that pathological tau accumulation is spatially related to blood vessels in AD. In addition, these data imply that blood vessels contribute to tau clearance and that vascular tau clearance is disrupted in regions with high tau accumulation.