Distribution Of Tau Research Articles

Biochemical Evidence for a Pathological Variant of Progressive Supranuclear Palsy

AbstractBackgroundTau proteins aggregate into spatially and morphologically distinct lesions in primary and secondary tauopathies. These signature lesions result from deposition of tau proteins that are distinctly modified via missense mutation and/or post‐translational modification for each disease strain. Identifying the unique tau protein abnormalities that lead to specific neurodegenerative diseases is beneficial in their early diagnosis and treatment. This is especially true for Progressive Supranuclear Palsy a primary tauopathy with clinical symptoms mirroring Parkinsonian syndromes and frontotemporal dementias.MethodBiochemical analysis of tau aggregates from patients with a pathological diagnosis of Progressive Supranuclear Palsy (n = 60) demonstrate that the tau protein modifications observed in this disease result from tau that is specifically modified and thereby forms the basis of the distinct disease strains observed. Here data collected using the sarkosyl‐insoluble tau fractions from tissue samples of pathologically diagnosed patients with Progressive Supranuclear Palsy without comorbidities allows for the direct observation of the modifications. Most interesting is the variability of the tau proteins that actually accumulate for this disease opening up the possibility that tau strains may exist within any given tauopathy even as the clinical manifestations appear similar. This indicates that early and specific identification and detection of these strains is critical for the development of therapies for these diseases.ResultExtraction and examination of sarkosyl‐insoluble tau proteins from deceased patients pathologically diagnosed with Progressive Supranuclear Palsy indicate that multiple tau strains exist within this primary tauopathy. Western blotting of these extracts from patient tissues demonstrates a unique banding pattern of insoluble tau in a subset of the cases that exhibit extreme hyperphosphorylation as indicated by additional high molecular weight tau banding. These patients also had an earlier age of onset and age of death indicating a more aggressive disease strain. Additional data is presented comparing the structure and seeding capability of this insoluble tau and the distribution and burden of insoluble tau in these Progressive Supranuclear Palsy patients compared to those with typical onset and insoluble tau signature.ConclusionMultiple pathological tau strains exist in Progressive Supranuclear Palsy.

Discriminative power of multi‐PET tracer approach targeting reactive astrogliosis, tau pathology, and dopaminergic impairment in 4R primary tauopathies

AbstractBackgroundThe 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are described as dementias with parkinsonian syndrome. Even if they are proven to represent clinically different entities, their complex neuropathology and common hallmarks often make the differential clinical diagnosis of CBD and PSP challenging. The highly entangled astrocytic and tau pathologies observed in these diseases are however displaying unique disparities which might unravel specific neuropathological profiles for each disease. The multi‐PET tracer approach applied in the present study in postmortem brain tissue might provide new mechanistic insights. We recently demonstrated that the second‐generation tau PET tracer, 3H‐PI2620 had a discriminative potential in CBD, PSP, and Alzheimer’s disease (AD) brains (Malarte et al. Mol. Psychiatry. 2022). To further understand the interaction between tau spatial distribution and its potential effects on astrocytic reactivity, we conducted a comparative multi‐tracer investigation in CBD, PSP, AD, and control brains using novel tau and astrocytic tracers. To gain a deeper insight into the relationship between tau, astrogliosis, and concomitant motor impairments, we also studied the interaction with the dopaminergic system.MethodWe performed autoradiography studies on large frozen hemispherical brain tissue of CBD, PSP, AD, and control cases using the tau PET tracer 3H‐PI2620, in comparison to astrocytic tracers (3H‐BU99008 and 3H‐Deprenyl) and dopaminergic tracers (3H‐Raclopride and 3H‐FE‐PE2I). We also analyzed the regional distribution of these tracers in small adjacent frozen brain sections of pathologically specific brain regions (globus pallidus, putamen, caudate, frontal cortex, medulla oblongata). We also performed saturation studies with 3H‐BU99008 and 3H‐Deprenyl on CBD and PSP brain homogenatesResultOur preliminary results are promising and suggest high astrogliosis measured by 3H‐BU99008 and 3H‐Deprenyl in large frozen autoradiography in CBD and PSP brains, and with different binding intensities in different brain regions comparable with regional 3H‐PI2620 binding. 3H‐BU99008 and 3H‐Deprenyl both highlighted two binding sites in the putamen of CBD cases, but only one site in PSP.ConclusionOngoing multi‐PET tracer studies targeting different pathological hallmarks of CBD and PSP tauopathies will improve differentiation and provide new knowledge regarding the spatial distribution of tau and its correlation with astrogliosis and the dopaminergic system in primary tauopathies.

Discriminative power of multi‐PET tracer approach targeting reactive astrogliosis, tau pathology, and dopaminergic impairment in 4R primary tauopathies

AbstractBackgroundThe 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are described as dementias with parkinsonian syndrome. Even if they are proven to represent clinically different entities, their complex neuropathology and common hallmarks often make the differential clinical diagnosis of CBD and PSP challenging. The highly entangled astrocytic and tau pathologies observed in these diseases are however displaying unique disparities which might unravel specific neuropathological profiles for each disease. The multi‐PET tracer approach applied in the present study in postmortem brain tissue might provide new mechanistic insights. We recently demonstrated that the second‐generation tau PET tracer, 3H‐PI2620 had a discriminative potential in CBD, PSP, and Alzheimer’s disease (AD) brains (Malarte et al. Mol. Psychiatry. 2022). To further understand the interaction between tau spatial distribution and its potential effects on astrocytic reactivity, we conducted a comparative multi‐tracer investigation in CBD, PSP, AD, and control brains using novel tau and astrocytic tracers. To gain a deeper insight into the relationship between tau, astrogliosis, and concomitant motor impairments, we also studied the interaction with the dopaminergic system.MethodWe performed autoradiography studies on large frozen hemispherical brain tissue of CBD, PSP, AD, and control cases using the tau PET tracer 3H‐PI2620, in comparison to astrocytic tracers (3H‐BU99008 and 3H‐Deprenyl) and dopaminergic tracers (3H‐Raclopride and 3H‐FE‐PE2I). We also analyzed the regional distribution of these tracers in small adjacent frozen brain sections of pathologically specific brain regions (globus pallidus, putamen, caudate, frontal cortex, medulla oblongata). We also performed saturation studies with 3H‐BU99008 and 3H‐Deprenyl on CBD and PSP brain homogenatesResultOur preliminary results are promising and suggest high astrogliosis measured by 3H‐BU99008 and 3H‐Deprenyl in large frozen autoradiography in CBD and PSP brains, and with different binding intensities in different brain regions comparable with regional 3H‐PI2620 binding. 3H‐BU99008 and 3H‐Deprenyl both highlighted two binding sites in the putamen of CBD cases, but only one site in PSP.ConclusionOngoing multi‐PET tracer studies targeting different pathological hallmarks of CBD and PSP tauopathies will improve differentiation and provide new knowledge regarding the spatial distribution of tau and its correlation with astrogliosis and the dopaminergic system in primary tauopathies.

Analysis of Tau heterogeneity and proteome‐wide changes in Alzheimer’s Disease at the single‐molecule level

AbstractBackgroundThe molecular heterogeneity of Tau is a critical contributor to Alzheimer’s disease (AD) progression and pathology. Currently, very little is known about the prevalence or impact of the diverse collection of Tau proteoforms. Additionally, individual proteoforms may have different interactions or frequencies within the broader proteome. Here, we detected and analyzed Tau proteoforms in the context of the broader proteome in model systems using a novel single‐molecule proteomic analysis platform with future applicability in AD samples.MethodWe used a single‐molecule proteomic analysis platform that leverages a set of target isoform specific and target PTM specific affinity reagents combined with novel instrumentation, single‐molecule biochemistry, and machine learning bioinformatics to enable deep proteoform and broad proteome analysis. In this study, we first evaluated the proteoform distribution of Tau using commercially available antibody reagents. Proteoform heterogeneity was compared (specifically splicing and phosphorylation variants) in both healthy and diseased samples. Then, total protein counts were assessed across the proteome using Protein Identification by Short‐epitope Mapping (PrISM), which leverages proprietary multi‐affinity probes designed to recognize short epitopes and a machine learning algorithm that decodes binding of hundreds of multi‐affinity probes into protein quantifications.ResultThe approach was evaluated by first measuring defined mixtures of recombinant Tau proteins. Next, we examined Tau enriched from induced pluripotent stem cell (iPSC)‐derived neurons and tau‐expressing cell lines. The platform revealed the molecular heterogeneity of Tau proteoforms missed by bulk measurements and peptide‐centric proteomics approaches. The proteoform data was then supplemented with broader proteome analysis in order to identify proteome‐wide changes – differences in proteins and pathways due to or in combination with specific Tau proteoforms and disease.ConclusionUnderstanding the biology of complex diseases like AD and other Tauopathies depends on understanding both the specific Tau proteoforms that exist at baseline and in disease as well as the pathways and processes impacted in the proteome. Single‐molecule tools that can analyze proteoforms in depth and the proteome broadly and link molecular signatures to disease states are essential. These tools will enable improved biomarkers, improved understanding of disease, and improved therapies for Alzheimer’s disease in the future.

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.

A two‐parameter parsimonious bathtub model for the analysis of system failure times with illustrations to reliability data

AbstractIn this study, a two‐parameter, upper‐bounded probability distribution called the tau distribution is introduced and its applications in reliability engineering are presented. Each of the parameters of the tau distribution has a clear semantic meaning. Namely, one of them determines the upper bound of the distribution, while the value of the other parameter influences the shape of the cumulative distribution function. A remarkable property of this new probability distribution is that its probability density function, survival function, hazard rate function (HRF), and quantile function can all be expressed in terms of its cumulative distribution function. The HRF of the proposed probability distribution can exhibit an increasing trend and various bathtub shapes with or without a low and long‐flat phase (useful time phase), which makes this new distribution suitable for modeling a wide range of real‐world problems. The constraint maximum likelihood estimation, percentile estimation, approximate Bayesian computation, and approximate quantile estimation computation are proposed to calculate the unknown parameters of the model. The suitability of the estimation methods is verified with the aid of simulation and real‐world data results. The modeling capability of the tau distribution was compared with that of some well‐known two‐ and three‐parameter probability distributions using two data sets known from the literature of reliability engineering: time between failures data of a machining center, and time to failure of data acquisition system cards. Based on empirical results, the new distribution may be viewed as a viable competitor to the Weibull, Gamma, Chen, and modified Weibull distributions.

Effects of the APOEɛ4 Allele on the Relationship Between Tau and Amyloid-β in Early- and Late-Onset Alzheimer's Disease.

Little is known regarding the differential effects of the apolipoprotein E (APOE) ɛ4 on the regional topography of amyloid and tau in patients with both early-onset (EOAD) and late-onset Alzheimer's disease (LOAD). To compare the distribution and association of tau, amyloid, and cortical thickness among groups classified by the presence of APOEɛ4 allele and onset age. A total of 165 participants including 54 EOAD patients (29 ɛ4-; 25 ɛ4+), 45 LOAD patients (21 ɛ4-; 24 ɛ4+), and 66 age-matched controls underwent 3T MRI, 18F-THK5351 (THK) and 18F-flutemetamol (FLUTE) PET scans, APOE genotyping, and neuropsychological tests. Data for voxel-wise and standardized uptake values from PET scans were analyzed in the context of APOE and age at onset. EOAD ɛ4- patients showed greater THK retention in the association cortices, whereas their EOAD ɛ4+ counterparts had more retention in medial temporal areas. THK topography of LOAD ɛ4+ was similar to EOAD ɛ4 + . THK correlated positively with FLUTE and conversely with mean cortical thickness, being lowest in EOAD ɛ4-, highest in LOAD ɛ4-, and modest in ɛ4+ groups. Even in the APOEɛ4+ groups, THK tended to correlate with FLUTE and mean cortical thickness in the inferior parietal region in EOAD and in the medial temporal region in LOAD. LOAD ɛ4- manifested with prevalent small vessel disease markers and the lowest correlation between THK retention and cognition. Our observations suggest the differential effects of the APOEɛ4 on the relationship between tau and amyloid in EOAD and LOAD.

The heterogeneity of asymmetric tau distribution is associated with an early age at onset and poor prognosis in Alzheimer’s disease

AbstractBackgroundThis study aimed to investigate whether an asymmetric tau distribution on PET images could be associated with clinical characteristics and prognosis in prodromal and/or clinical Alzheimer’s disease (AD).MethodThe testing cohort consisted of 60 patients with mild cognitive impairment due to AD and AD dementia from the Alzheimer’s Disease Neuroimaging Initiative – who underwent tau PET imaging with the first‐generation tau tracer [18F]flortaucipir. The validation cohort consisted of an independent sample of 67 patients enrolled from the Shanghai Memory Study who underwent PET tau imaging with the second‐generation tau tracer [18F]APN‐1607. Based on the absolute global tau interhemispheric differences, each cohort was divided into two groups (asymmetric versus symmetric tau distribution). The two groups were cross‐sectionally compared in terms of demographic and cognitive characteristics, as well as pathological burden. The cognitive trajectories of cognitive decline were analyzed longitudinally.ResultFourteen patients (23.3%) in the testing cohort and 26 (38.8%) in the validation cohort showed an asymmetric tau distribution. In both cohorts, cross‐sectional results consistently revealed that an asymmetric tau distribution was associated with an earlier age at disease onset and more severe tau and amyloid burden (Fig 1). In longitudinal analyses, patients with an asymmetric tau distribution were characterized by a steeper cognitive decline (Fig 2).ConclusionAn asymmetric tau distribution on PET images was consistently associated with an earlier age at onset and more severe pathological features of AD in two independent cohorts. Additionally, this imaging biomarker was longitudinally associated with a more rapid trajectory of cognitive decline.

Comparative assessment of regional tau distribution by Tau-PET and Post-mortem neuropathology in a representative set of Alzheimer's & frontotemporal lobar degeneration patients.

Flortaucipir (FTP) PET is a key imaging technique to evaluate tau burden indirectly. However, it appears to have greater utility for 3R+4R tau found in Alzheimer's disease (AD), compared to other non-AD tauopathies. The purpose of this study is to determine how flortaucipir uptake links to neuropathologically determined tau burden in AD and non-AD tauopathies. We identified nine individuals who had undergone antemortem tau-PET and postmortem neuropathological analyses. The cohort included three patients with low, moderate, and high AD neuropathologic changes (ADNC), five patients with a non-AD tauopathy (one Pick's disease, three progressive supranuclear palsies, and one globular glial tauopathy), and one control without ADNC. We compared regional flortaucipir PET uptake with tau burden using an anti-AT8 antibody. There was a very good correlation between flortaucipir uptake and tau burden in those with ADNC although, in one ADNC patient, flortaucipir uptake and tau burden did not match due to the presence of argyrophilic grains disease. Non-AD patients showed lower flortaucipir uptake globally compared to ADNC patients. In the non-AD patients, some regional associations between flortaucipir uptake and histopathological tau burden were observed. Flortaucipir uptake is strongly linked to underlying tau burden in patients with ADNC but there are instances where they do not match. On-the-other hand, flortaucipir has a limited capacity to represent histopathological tau burden in non-AD patients although there are instances where regional uptake correlates with regional tau burden. There is a definite need for the development of future generations of tau-PET ligands that can detect non-AD tau.

Predictive blood biomarkers and brain changes associated with age-related cognitive decline.

Growing evidence supports the use of plasma levels of tau phosphorylated at threonine 181, amyloid-β, neurofilament light and glial fibrillary acidic protein as promising biomarkers for Alzheimer's disease. While these blood biomarkers are promising for distinguishing people with Alzheimer's disease from healthy controls, their predictive validity for age-related cognitive decline without dementia remains unclear. Further, while tau phosphorylated at threonine 181 is a promising biomarker, the distribution of this phospho-epitope of tau in the brain is unknown. Here, we tested whether plasma levels of tau phosphorylated at threonine 181, amyloid-β, neurofilament light and fibrillary acidic protein predict cognitive decline between ages 72 and 82 in 195 participants in the Lothian birth cohorts 1936 study of cognitive ageing. We further examined post-mortem brain samples from temporal cortex to determine the distribution of tau phosphorylated at threonine 181 in the brain. Several forms of tau phosphorylated at threonine 181 have been shown to contribute to synapse degeneration in Alzheimer's disease, which correlates closely with cognitive decline in this form of dementia, but to date, there have not been investigations of whether tau phosphorylated at threonine 181 is found in synapses in Alzheimer's disease or healthy ageing brain. It was also previously unclear whether tau phosphorylated at threonine 181 accumulated in dystrophic neurites around plaques, which could contribute to tau leakage to the periphery due to impaired membrane integrity in dystrophies. Brain homogenate and biochemically enriched synaptic fractions were examined with western blot to examine tau phosphorylated at threonine 181 levels between groups (n = 10-12 per group), and synaptic and astrocytic localization of tau phosphorylated at threonine 181 were examined using array tomography (n = 6-15 per group), and localization of tau phosphorylated at threonine 181 in plaque-associated dystrophic neurites with associated gliosis were examined with standard immunofluorescence (n = 8-9 per group). Elevated baseline plasma tau phosphorylated at threonine 181, neurofilament light and fibrillary acidic protein predicted steeper general cognitive decline during ageing. Further, increasing tau phosphorylated at threonine 181 over time predicted general cognitive decline in females only. Change in plasma tau phosphorylated at threonine 181 remained a significant predictor of g factor decline when taking into account Alzheimer's disease polygenic risk score, indicating that the increase of blood tau phosphorylated at threonine 181 in this cohort was not only due to incipient Alzheimer's disease. Tau phosphorylated at threonine 181 was observed in synapses and astrocytes in both healthy ageing and Alzheimer's disease brain. We observed that a significantly higher proportion of synapses contain tau phosphorylated at threonine 181 in Alzheimer's disease relative to aged controls. Aged controls with pre-morbid lifetime cognitive resilience had significantly more tau phosphorylated at threonine 181 in fibrillary acidic protein-positive astrocytes than those with pre-morbid lifetime cognitive decline. Further, tau phosphorylated at threonine 181 was found in dystrophic neurites around plaques and in some neurofibrillary tangles. The presence of tau phosphorylated at threonine 181 in plaque-associated dystrophies may be a source of leakage of tau out of neurons that eventually enters the blood. Together, these data indicate that plasma tau phosphorylated at threonine 181, neurofilament light and fibrillary acidic protein may be useful biomarkers of age-related cognitive decline, and that efficient clearance of tau phosphorylated at threonine 181 by astrocytes may promote cognitive resilience.

Tau accumulates differently in four subtypes of Alzheimer's disease

AbstractBackgroundHeterogeneity in Alzheimer's disease (AD) has been reported on the basis of clinical, neuropathological, and neuroimaging data. However, most of the indices, including cerebral atrophy evaluated using magnetic resonance imaging and amyloid β (Aβ) accumulation detected using positron emission tomography (PET), lack sensitivity, and specificity for categorization.AimHerein, we used a novel PET ligand for tau to estimate the differential distribution of tau in the subtypes of AD.MethodsPatients with posterior cortical atrophy (PCA; n = 3), frontal variant of AD (FAD; n = 1), logopenic variant primary progressive aphasia (LPPA; n = 2), typical AD (TAD; n = 6), and healthy controls (HC; n = 12) were studied. Aβ and tau accumulation were evaluated using [11C]PiB and [11C]PBB3, respectively.ResultsAmyloid β accumulation was confirmed in all PCA, FAD, LPPA, and TAD cases. Tau accumulation was dominantly high in the occipital lobes in the PCA, strikingly high in the frontal lobes in the FAD, and moderately high in the angular gyrus of the dominant hemisphere in the LPPA. Tau accumulation in TAD cases was significantly higher than age‐dependent tau accumulation in HC in these subtype‐specific regions as well as in AD signature regions. Glucose utilization was reversely correlated with PBB3 accumulation in the subtype‐specific regions.ConclusionsTau accumulates differently in the four subtypes of AD, suggesting that tau pathology may be closely associated with unique clinical features.

Why slow axonal transport is bidirectional – can axonal transport of tau protein rely only on motor-driven anterograde transport?

Slow axonal transport (SAT) moves multiple proteins from the soma, where they are synthesized, to the axon terminal. Due to the great lengths of axons, SAT almost exclusively relies on active transport, which is driven by molecular motors. The puzzling feature of slow axonal transport is its bidirectionality. Although the net direction of SAT is anterograde, from the soma to the terminal, experiments show that it also contains a retrograde component. One of the proteins transported by SAT is the microtubule-associated protein tau. To better understand why the retrograde component in tau transport is needed, we used the perturbation technique to analyze how the full tau SAT model can be simplified for the specific case when retrograde motor-driven transport and diffusion-driven transport of tau are negligible and tau is driven only by anterograde (kinesin) motors. The solution of the simplified equations shows that without retrograde transport the tau concentration along the axon length stays almost uniform (decreases very slightly), which is inconsistent with the experimenal tau concentration at the outlet boundary (at the axon tip). Thus kinesin-driven transport alone is not enough to explain the empirically observed distribution of tau, and the retrograde motor-driven component in SAT is needed.

Measurement of Aβ Amyloid Plaques and Tau Protein in Postmortem Human Alzheimer’s Disease Brain by Autoradiography Using [18F]Flotaza, [125I]IBETA, [124/125I]IPPI and Immunohistochemistry Analysis Using QuPath

High-resolution scans of immunohistochemical (IHC) stains of Alzheimer's disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aβ plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aβ plaques and Tau is essential to understand the progression of AD pathology. Our goal was to develop a quantitative method for the analysis of IHC-autoradiography images. Postmortem anterior cingulate (AC) and corpus callosum (CC) from AD and control (CN) subjects were IHC stained with anti-Aβ for Aβ plaques and autoradiography with [18F]flotaza and [125I]IBETA for Aβ plaques. For Tau, [124I]IPPI, a new radiotracer, was synthesized and evaluated in the AD brain. For Tau imaging, brain slices were IHC stained with anti-Tau and autoradiography using [125I]IPPI and [124I]IPPI. Annotations for Aβ plaques and Tau using QuPath for training and pixel classifiers were generated to measure the percent of the area of Aβ plaques and Tau in each slice. The binding of [124I]IPPI was observed in all AD brains with an AC/CC ratio > 10. Selectivity to Tau was shown by blocking [124I]IPPI with MK-6240. Percent positivity for Aβ plaques was 4-15%, and for Tau, it was 1.3 to 35%. All IHC Aβ plaque-positive subjects showed [18F]flotaza and [125I]IBETA binding with a positive linear correlation (r2 > 0.45). Tau-positive subjects showed [124/125I]IPPI binding with a stronger positive linear correlation (r2 > 0.80). This quantitative IHC-autoradiography approach provides an accurate measurement of Aβ plaques and Tau within and across subjects.

Comparative phytochemical studies on the roots of Polygala azizsancarii and P. peshmenii and neuroprotective activities of the two xanthones

Six known sucrose mono-, di- and triesters and five xanthone derivatives were isolated from the roots of Polygala peshmenii Eren, Parolly, Raus & Kürschner which is a narrow species endemic to Türkiye. Among the xanthones, 1,7-dihydroxy-2,3-methylenedioxy-5,6-dimethoxy-xanthone is an undescribed compound isolated for the first time from a natural source. The studies on the roots of P. azizsancarii Dönmez have resulted in the isolation of four known compounds including sucrose mono-, di- and triesters. The structures of the sucrose esters and xanthones isolated from P. azizsancarii and P. peshmenii were established by spectroscopic methods, including 1D-NMR (1H NMR, 13C NMR, DEPT-135), 2D-NMR (COSY, NOESY, HSQC, HMBC). Neuroprotective activities of two xanthones, 1,3,6-trihydroxy-2,5,7-trimethoxyxanthone and 3-O-β-D-glucopyranosyloxy-1,6-dihydroxy-2,5,7-trimethoxyxanthone isolated from the roots of P. azizsancarii were evaluated in vitro using in a cellular model of Alzheimer's disease. SKNAS human neuroblastoma cells were used in the study and treated with different consecrations of Aβ₂₅₋₃₅ oligomer for up to 48 h. Cell viability was evaluated using MTT assay. The distribution of β-amyloid, α-synuclein, tau, JAK2, STAT3, caspase 3 and BMP-2 were investigated using indirect immunoperoxidase staining. Our results suggested that both xanthones control tau aggregation with no effect on β-amyloid plaque formation. In addition, for neuronal pathophysiology in AD cell model, decreased distributions of JAK/STAT3 and BMP2 signaling pathways were demonstrated, therefore they play a role in the protective effect on neurons in neurodegenerative disease. A significant decrease in caspase 3 immunoreactivity was detected after the administration of both compounds in AD cells. Therefore, both compounds control neuronal pathophysiology and rescue cell death in AD disease.

The heterogeneity of asymmetric tau distribution is associated with an early age at onset and poor prognosis in Alzheimer’s disease

PurposeLeft-right asymmetry, an important feature of brain development, has been implicated in neurodegenerative diseases, although it’s less discussed in typical Alzheimer’s disease (AD). We sought to investigate whether asymmetric tau deposition plays a potential role in AD heterogeneity. MethodsTwo independent cohorts consisting of patients with mild cognitive impairment due to AD and AD dementia with tau PET imaging were enrolled [the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort with 18F-Flortaucipir, the Shanghai Memory Study (SMS) cohort with 18F-Florzolotau]. Based on the absolute global tau interhemispheric differences, each cohort was divided into two groups (asymmetric versus symmetric tau distribution). The two groups were cross-sectionally compared in terms of demographic, cognitive characteristics, and pathological burden. The cognitive decline trajectories were analyzed longitudinally. ResultsFourteen (23.3%) and 42 (48.3%) patients in the ADNI and SMS cohorts showed an asymmetric tau distribution, respectively. An asymmetric tau distribution was associated with an earlier age at disease onset (proportion of early-onset AD: ADNI/SMS/combined cohorts, p = 0.093/0.026/0.001) and more severe pathological burden (i.e., global tau burden: ADNI/SMS cohorts, p < 0.001/= 0.007). And patients with an asymmetric tau distribution were characterized by a steeper cognitive decline longitudinally (i.e., the annual decline of Mini-Mental Status Examination score: ADNI/SMS/combined cohorts, p = 0.053 / 0.035 / < 0.001). ConclusionsAsymmetry in tau deposition, which may be associated with an earlier age at onset, more severe pathological burden, and a steeper cognitive decline, is potentially an important characteristic of AD heterogeneity.

Interregional Gene Expression Analysis Identifies Signature of Cerebellar Resistance to AD Tauopathy

AbstractBackgroundThe appearance of neurofibrillary tangles (NFTs) reflects both their spatial location within affected connectivity networks and the intrinsic vulnerability of neuronal populations to their formation. Here we disaggregate human gene expression data on the basis of connectivity to identify differentially expressed genes (DEGs) associated with neuroprotection against tauopathy.MethodTranscriptomic analysis focused on prefrontal cortex (PFC) and cerebellum, which both associate with the default mode and other AD‐affected networks. However, whereas PFC is vulnerable to tauopathic neurodegeneration, the cerebellum atrophies without NFT formation or cell loss. To identify candidate mediators of selective vulnerability, gene expression patterns in both regions from AD and control brains were calculated and then subjected to cell‐type specific enrichment analysis (CSEA), gene set enrichment analysis (GSEA), and transcription factor interaction network (TFIN) analysis. To validate candidate effector genes, prioritized chaperones were incubated with tau protein to test for suppression of biochemically induced fibrillization. The resulting distribution of soluble and aggregated tau was measured by sedimentation.ResultsCSEA revealed DEGs that changed in parallel between regions originated primarily in glia and microglia. GSEA identified these as belonging to Gene Ontology (GO) categories associated with host response and ion homeostasis. Of 446 genes, 379 were linked in a TFIN, with the most central nodes including transcriptional regulators HBP1, EGR1, SERTAD1, and PER1. In contrast, DEGs changing in opposition were primarily neuronal. GSEA identified 14 heat shock genes, including nine chaperone proteins reported to regulate protein folding. Of 402 candidate vulnerability genes, 319 were linked in a TFIN, in which the most central hubs were long noncoding RNA NEAT1, and transcription factors BHLHE40, ZC3H10, and CREB3L4. Finally, aggregation and sedimentation of tau showed all nine chaperones antagonized biochemical fibrillization of 2N4R tau with octadecyl sulfate at substoichiometric ratios of chaperone to tau.ConclusionsOur study takes advantage of a selective vulnerability informed approach to gene expression and highlights the role of proteostasis and neuronal genes in protecting the cerebellum from tau lesions. This approach successfully identified biologically active effector genes and can be applied broadly to other neurodegenerative diseases featuring prion‐like pathology and will orient the field toward endogenous strategies of neuroprotection.

Lower in‐vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology

AbstractBackgroundCortical neurodegeneration is, along with Alzheimer’s Disease (AD) pathology, an important feature of AD, which correlates highly with tauopathy and cognitive decline. Post‐mortem data show that the locus coeruleus (LC) loses approximately 8.4% volume per cortical Braak stage. This work investigates whether LC integrity, as indexed by LC MRI signal intensity, is associated with cortical thickness, and whether this is exacerbated by the presence of AD pathology.MethodCross‐sectional data from 165 Harvard Aging Brain Study participants (age range=50‐94 years; female=∼60%; cognitively unimpaired: n=149, cognitively impaired: n=16; Table 1) who underwent 3T‐MRI, PiB‐PET (cut‐off=1.324 DVR) and T807‐PET scanning was selected. LC MRI signal intensity was assessed by normalizing the LC to the pontine tegmentum (reference region) for each individual and averaging clusters of 5 voxels with the highest intensities. Unilateral cortical thickness (CT) values were extracted utilizing the Desikan‐Killiany atlas (FreeSurfer 6) and averaged across hemispheres to obtain regional bilateral values. PET measures were corrected for partial‐volume effects. Associations between CT and i) LC intensity, or ii) LC intensity interacted with pathology (i.e., inferior temporal (IT) tau, entorhinal (EC) tau and global amyloid), were examined with bootstrapped linear regressions, while controlling for age, sex, and education, and applying FDR‐correction.ResultWe found a positive association between LC intensity and CT for medial and lateral temporal regions (p‐FDR&lt;0.05; Figure 1). Models interacting LC intensity with IT or EC tau revealed that lower LC intensity was associated with lower CT especially in temporal regions. This effect was greater in individuals with elevated tau (p‐FDR&lt;0.05; Figure 2‐3). Results still held after controlling for amyloid (p‐FDR&lt;0.05). Similarly, interacting LC intensity with amyloid showed a relation between lower LC intensity and lower CT in temporal and some occipital regions, which was stronger in individuals with elevated amyloid (p‐FDR&lt;0.05; Figure 4).ConclusionThis work demonstrates that lower LC integrity is associated with bilateral cortical thinning in regions aligning with the expected topographical distribution of tau in preclinical AD. Additionally, these spatial patterns are more widespread in individuals with elevated AD pathology. These results suggest that LC integrity is closely related to the downstream neurodegenerative sequela of AD pathology.

Multi‐tracer comparison in Alzheimer’s disease, Corticobasal Degeneration and Progressive Supranuclear Palsy brains

AbstractBackgroundRecent CryoEM studies in tauopathies clearly bought forward one more time the complexity of these pathologies, and showed that it goes beyond the tau isoforms. Tau PET tracers play an important role in the understanding of this aspect. We have observed in post‐mortem brain tissue from Alzheimer’s disease (AD) patients that the second‐generation of tau PET tracers 3H‐PI2620, 3H‐MK6240, 3H‐RO948, all show similar regional distribution, but also comparable binding affinities to multiple binding sites in AD brain large hemispherical tissue section autoradiography and homogenates. In vitro autoradiography can mirror the in vivo binding pattern of PET tracers and be useful in pre‐clinical validations. The aim of this study was to perform a comparative multi‐tracer study in AD, PSP, CBD and control brains with several second generation tau‐tracers to obtain a deeper insight into tau spatial distribution and discriminative power of tau tracers in degenerative proteinopathies. We also want to study how the binding of the tracers correlate with other pathological hallmarks such as amyloid‐β and reactive astrogliosis.Methodswe performed radioligand binding assays in brain homogenates, in small tissue sections and large frozen hemispherical brain sections autoradiography using tau PET tracers (3H‐PI2620, 3H‐MK6240, 3H‐RO948, and 3H‐JNJ067) in comparison to reactive astrogliosis PET tracers (3H‐BU99008 and 3H‐Deprenyl) and amyloid tracer (3H‐PIB).ResultsIn ongoing studies, 3H‐PI2620, 3H‐MK6240 and 3H‐RO948 clearly followed a two binding sites model in AD brains. 3H‐PI2620 bound to two binding sites in the frontal cortex of both AD and CBD but to one site in PSP brains, but in similar high affinity range in the three pathologies. 3H‐RO948 and 3H‐MK6240 showed low binding in comparison to 3H‐PI2620 in CBD and PSP.ConclusionTau PET tracers showed similar affinities to multiple binding sites and similar regional distribution in AD brains. 3H‐MK6240 and 3H‐RO948 displayed selectivity for AD brains, while 3H‐PI2620 also showed similar binding affinity for CBD and PSP brains. Ongoing studies with several PET tracers targeting different pathological hallmarks will increase possible discriminative properties and provide new knowledge on the spatial distribution of tau and its correlation with other biomarkers in different tauopathies.

Digital Pathology Investigation of SERPINA5‐Tau Protein Interaction in Alzheimer’s Disease and Primary Tauopathies

AbstractBackgroundWe recently discovered a novel tau binding partner, SERPINA5, to be upregulated in Alzheimer’s disease (AD) and co‐localize with corticolimbic tau distribution. As tau pathology is also observed in primary tauopathies, we hypothesized that SERPINA5 burden would mirror tau burden in these diseases. Thus, we sought to define the relationship between SERPINA5 and tau in primary tauopathies and compare this relationship to AD.MethodImmunohistochemistry was performed on the hippocampus or cingulate in 4 groups (n=6 per disease group): 1) AD, 2) 3R+4R primary age‐related tauopathy, 3) 4R tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grains disease), and 4) 3R tauopathy (Pick’s disease). Burden analyses for SERPINA5 and a phospho‐tau marker (AT8) were performed on digitized whole slide images.ResultVisual interpretation of SERPINA5 immunostaining identified both neuronal and glial inclusions that are commonly AT8‐positive in primary tauopathies. There were exceptions to this pattern such as SERPINA5‐positive Pick bodies being rarely observed. However, some pathologic structures, like ballooned neurons, were preferentially stained by SERPINA5. Quantitative analyses confirmed this observation with AT8 and SERPINA5 burden correlating in both the cingulate (R2=0.47, p&lt;0.0001, Figure 1a) and hippocampus (R2=0.74, p&lt;0.0001, Figure 1d). Nonparametric rank sum tests revealed majority of the primary tauopathies had less AT8 and SERPINA5 burden compared to AD in both the cingulate and hippocampus (Figure1b‐c, e‐f; Table 1).ConclusionSERPINA5 immunostaining patterns in primary tauopathies reflect tau immunostaining patterns. Our data suggests the SERPINA5‐tau interaction may not be specific for AD, which may implicate the role of SERPINA5 more broadly across tauopathies.

Baseline regional Tau distribution predicts fast cognitive decline in subjects with mild cognitive impairment

AbstractBackgroundNeurofibrillary tangles represent a pathological hallmark of AD that spreads throughout the brain in a relatively stereotypical spatio‐temporal fashion along Braak stages. Understanding the impact of regional Tau distribution and spread on future cognitive decline would be highly valuable for targeted patient selection and treatment strategy in drug development.MethodRegional flortaucipir (FTP) PET SUVR in 77 brain regions, and Braak stage regions I‐VI, were available from 638 ADNI subjects (89 AD, 117 MCI, 432 age‐matched normal controls). Baseline FTP data, processed at UC Berkeley, was partial volume corrected to reduce off‐target binding contamination. Braak stage II (i.e., hippocampus) was excluded from the analysis due to known off‐target binding in this region.A machine‐learning (ML) approach via stochastic gradient boosting was applied to determine the characteristics of regional Tau distribution that uniquely reflect AD relative to control subjects. This signature was then applied to PET scans of an independent group of 117 MCI subjects to predict their 24‐month cognitive decline, as defined by an increase in the clinical dementia rating sum of boxes (CDR‐SB). MCI subjects predicted to have ‘control‐like’ Tau deposition signature were considered as slow cognitive decliners while those predicted to have ‘AD‐like’ signature were considered as fast decliners. Prediction performance was evaluated and the regions of Tau deposition indicative of faster cognitive decline were identified.ResultMCI subjects predicted as fast cognitive decliners had odds ratio of 7.3 relative to those predicted as slow decliners (7.3‐fold greater odds of decline), with the median and 75th percentile increase in CDR‐SB of 1 and 3 respectively, compared to an increase of 0 and 0.5 among those predicted as slow decliners. Subjects with Tau deposition in Braak I (entorhinal cortex) and Braak III at baseline, and particularly in the amygdala, were predicted to be fast decliners. Further presence of Tau in parahippocampal, fusiform and precuneus regions at baseline were strongly associated with fast cognitive decline.ConclusionThe nature of baseline regional Tau distribution in MCI subjects is a strong indicator of fast cognitive decline that can help inform targeted patient selection and treatment strategy in drug development.