Accumulation Of Tau Protein Research Articles

Modifying Alzheimer's disease pathophysiology with photobiomodulation: model, evidence, and future with EEG-guided intervention.

This manuscript outlines a model of Alzheimer's Disease (AD) pathophysiology in progressive layers, from its genesis to the development of biomarkers and then to symptom expression. Genetic predispositions are the major factor that leads to mitochondrial dysfunction and subsequent amyloid and tau protein accumulation, which have been identified as hallmarks of AD. Extending beyond these accumulations, we explore a broader spectrum of pathophysiological aspects, including the blood-brain barrier, blood flow, vascular health, gut-brain microbiodata, glymphatic flow, metabolic syndrome, energy deficit, oxidative stress, calcium overload, inflammation, neuronal and synaptic loss, brain matter atrophy, and reduced growth factors. Photobiomodulation (PBM), which delivers near-infrared light to selected brain regions using portable devices, is introduced as a therapeutic approach. PBM has the potential to address each of these pathophysiological aspects, with data provided by various studies. They provide mechanistic support for largely small published clinical studies that demonstrate improvements in memory and cognition. They inform of PBM's potential to treat AD pending validation by large randomized controlled studies. The presentation of brain network and waveform changes on electroencephalography (EEG) provide the opportunity to use these data as a guide for the application of various PBM parameters to improve outcomes. These parameters include wavelength, power density, treatment duration, LED positioning, and pulse frequency. Pulsing at specific frequencies has been found to influence the expression of waveforms and modifications of brain networks. The expression stems from the modulation of cellular and protein structures as revealed in recent studies. These findings provide an EEG-based guide for the use of artificial intelligence to personalize AD treatment through EEG data feedback.

Histological and neuroimaging comparison of SMART syndrome versus focal neuronal gigantism.

Two of the rarest radiation-induced adverse effects are focal neuronal gigantism (FNG) and SMART syndrome (stroke-like migraine attacks after radiation therapy). Both conditions develop years, and sometimes decades, after receipt of therapeutic radiation to the brain. To date, there are only 3 previously reported cases of FNG, all of which describe cortical thickening, enlarged "hypertrophic" neurons, and neuronal cytological changes. No detailed studies exist of histological features of SMART or the comparison between FNG and SMART. In this study, we contrast histological and neuroimaging features of 3 FNG vs. 4 SMART cases, the latter diagnosed by a neuroradiologist, neurooncologist, and/or neurosurgeon. We confirm the cortical thickening, dyslamination, neuronal cytomegaly, and gliosis in FNG vs. cortical architectural preservation and normal neuronal cytology in SMART, although both showed gliosis, scattered neurons with cytoplasmic accumulation of tau and neurofibrillary protein and variable co-existence of other radiation-induced lesions. Both conditions lacked significant inflammation or consistent small vessel hyalinization throughout the entire resection specimen. The absence of pathognomonic histologic alterations in SMART cases suggests underlying vascular dysregulation. Despite differing histology, some overlap may exist in neuroimaging features. Molecular assessment conducted in 2 cases of FNG was negative for significant alterations including in the MAPK pathway.

The identification of a Distinct Astrocyte Subtype that Diminishes in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the presence of two hallmark pathologies: the accumulation of Amyloid beta (Aβ) and tau proteins in the brain. There is a growing body of evidence suggesting that astrocytes, a type of glial cell in the brain, play crucial roles in clearing Aβ and binding to tau proteins. However, due to the heterogeneity of astrocytes, the specific roles of different astrocyte subpopulations in response to Aβ and tau remain unclear. To enhance the understanding of astrocyte subpopulations in AD, we investigated astrocyte lineage cells based on single-nuclei transcriptomic data obtained from both human and mouse samples. We characterized the diversity of astrocytes and identified global and subpopulation-specific transcriptomic changes between control and AD samples. Our findings revealed the existence of a specific astrocyte subpopulation marked by low levels of GFAP and the presence of AQP4 and CD63 expression, which showed functional enrichment in Aβ clearance and tau protein binding, and diminished in AD. We verified this type of astrocytes in mouse models and in AD patient brain samples. Furthermore, our research also unveiled significant alterations of the ligand-receptor interactions between astrocytes and other cell types. These changes underscore the complex interplay between astrocytes and neighboring cells in the context of AD. Overall, our work gives insights into astrocyte heterogeneity in the context of AD and reveals a distinct astrocyte subpopulation that holds potential for therapeutic interventions in AD. Targeting specific astrocyte subpopulations may offer new avenues for the development of novel treatments for AD.

Is it possible to reduce glial activation in an old taupathia mouse model by deletion of microglial Hemoxygenase‐1?

Tauopathies such as Alzheimer's disease are characterized by the accumulation of neurotoxic aggregates of tau protein. With aging and, especially, in Alzheimer's patients, the inducible enzyme heme oxygenase 1 (HO‐1) progressively increases in microglia, causing iron accumulation, neuroinflammation, and neurodegeneration. The retina is an organ that can be readily accessed and can reflect changes that occur in the brain. In this context, we evaluated how the lack of microglial HO‐1, using mice that do not express HO‐1 in microglia (HMO‐KO), impacts retinal macro and microgliosis of aged subjects (18 months old mice) subjected to tauopathy by intrahippocampal delivery of AAV‐hTauP301L (TAU). Our results show that although tauopathy, measured as anti‐TAUY9 and anti‐AT8 positive immunostaining, was not observed in the retina of WT‐TAU or HMO‐KO + TAU mice, a morphometric study of retinal microglia and macroglia showed significant retinal changes in the TAU group compared to the WT group, such as: (i) increased number of activated microglia, (ii) retraction of microglial processes, (iii) increased number of CD68+ microglia, and (iv) increased retinal area occupied by GFAP (AROA) and C3 (AROC3). This retinal inflammatory profile was reduced in HMO‐KO + TAU mice. Therefore, a reduction of microglial HO‐1 could be beneficial to prevent tauopathy‐induced neuroinflammation.

Measuring Antibody-Mediated Tau Fibril Uptake in Microglia by Flow Cytometry.

Microglia are brain-resident phagocytic cells, considered to be the innate immune cells of the central nervous system. Microglia respond to both infectious pathogens in the brain and sterile cellular debris, including the proteinaceous aggregates that accumulate in the brains of patients with Alzheimer's disease (AD). Microtubule-associated protein Tau is an intracellular protein that self-aggregates into neurofibrillary tangles in Alzheimer's disease and many other neurodegenerative diseases. Ongoing clinical trials are testing whether therapeutic antibodies specific to Tau protein aggregates can reduce pathological protein deposition and improve the course of disease. Data suggest that Tau-specific antibodies act on extracellular Tau aggregates by promoting uptake into microglia cells and thus preventing its prion-like spread to unaffected neurons. Here we describe a protocol to test the effect of Tau-specific antibodies on Tau uptake into microglia by flow cytometry. Recombinant Tau protein is fibrillized in vitro and tagged with a fluorescent label. Then, fibrillized Tau is incubated with the antibody of interest and applied to microglial cells in culture. Uptake of Tau into microglia is then assessed by measuring fluorescence intensity by flow cytometry. With slight modifications, this assay can be used to test effects of many antibodies, various Tau protein compositions, and different microglial sources in a high-throughput format.

Application of single-molecule analysis to singularity phenomenon of cells.

Single-molecule imaging in living cells is an effective tool for elucidating the mechanisms of cellular phenomena at the molecular level. However, the analysis was not designed for throughput and requires high expertise, preventing it from reaching large scale, which is necessary when searching for rare cells that induce singularity phenomena. To overcome this limitation, we have automated the imaging procedures by combining our own focusing device, artificial intelligence, and robotics. The apparatus, called automated in-cell single-molecule imaging system (AiSIS), achieves a throughput that is a hundred-fold higher than conventional manual imaging operations, enabling the analysis of molecular events by individual cells across a large population. Here, using AiSIS, we demonstrate the single-molecule imaging of molecular behaviors and reactions related to tau protein aggregation, which is considered a singularity phenomenon in neurological disorders. Changes in the dynamics and kinetics of molecular events were observed inside and on the basal membrane of cells after the induction of aggregation. Additionally, to detect rare cells based on the molecular behavior, we developed a method to identify the state of individual cells defined by the quantitative distribution of molecular mobility and clustering. Using this method, cellular variations in receptor behavior were shown to decrease following ligand stimulation. This cell state analysis based on large-scale single-molecule imaging by AiSIS will advance the study of molecular mechanisms causing singularity phenomena.

Tryptophan Metabolism in Alzheimer's Disease with the Involvement of Microglia and Astrocyte Crosstalk and Gut-Brain Axis.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by extracellular Amyloid Aβ peptide (Aβ) deposition and intracellular Tau protein aggregation. Glia, especially microglia and astrocytes are core participants during the progression of AD and these cells are the mediators of Aβ clearance and degradation. The microbiota-gut-brain axis (MGBA) is a complex interactive network between the gut and brain involved in neurodegeneration. MGBA affects the function of glia in the central nervous system (CNS), and microbial metabolites regulate the communication between astrocytes and microglia; however, whether such communication is part of AD pathophysiology remains unknown. One of the potential links in bilateral gut-brain communication is tryptophan (Trp) metabolism. The microbiota-originated Trp and its metabolites enter the CNS to control microglial activation, and the activated microglia subsequently affect astrocyte functions. The present review highlights the role of MGBA in AD pathology, especially the roles of Trp per se and its metabolism as a part of the gut microbiota and brain communications. We (i) discuss the roles of Trp derivatives in microglia-astrocyte crosstalk from a bioinformatics perspective, (ii) describe the role of glia polarization in the microglia-astrocyte crosstalk and AD pathology, and (iii) summarize the potential of Trp metabolism as a therapeutic target. Finally, we review the role of Trp in AD from the perspective of the gut-brain axis and microglia, as well as astrocyte crosstalk, to inspire the discovery of novel AD therapeutics.

Mechanistic Insights into Tau Protein-Mediated Regulation of Oxidative Stress.

Abnormal hyperphosphorylation and microtubule-associated protein tau aggregation development in the brain are characteristics of neurodegenerative diseases referred to as tauopathies, which include Alzheimer's disease (AD). The current review summarizes the complex relationships that exist between oxidative stress and tau illness, with particular attention to the roles played by the tau protein, reactive oxygen species and their consequences, and tau phosphorylation and oxidative stress. Two key elements of detrimental cycle that are critical in neurodegenerative tauopathies are tau hyperphosphorylation and oxidative stress. When tau and microtubules are not connected properly, microtubule instability, issues with microtubule transport, and ultimately neuronal death result. While the causes of the more prevalent sporadic late-onset variants and the connections between tau hyperphosphorylation and neurodegeneration remain largely unknown, mutations in the microtubule-associated protein tau (MAPT) gene have been identified in familial cases of early-onset tauopathies. Another detrimental feature of tauopathies is oxidative stress, but the exact role it plays in the development of the disease is unclear. The source of reactive oxygen species (ROS), which lead to oxidative stress within neural tissue, remains an unresolved topic. Although mitochondria have historically been thought to be a primary source of oxidative stress, microglial cells have recently been discovered to create reactive oxygen species in tauopathies. In conclusion, enhancing our comprehension of the impact of oxidative stress on various diseases could facilitate the identification of new disease markers and lead to the formulation of treatment strategies aimed at halting, reversing, or mitigating disease progression.

CRISPR-Cas9: A Promising Tool in Developing Alzheimer’s Disease Treatment

Alzheimer’s disease (AD) impacts millions of people worldwide, causing cognitive impairment that can get more and more severe as the patients age. Such a disease can also severely impact patients’ lives in the late stage. AD is a sporadic and familial disease. Beta-amyloid (Aβ) and hyperphosphorylated tau protein aggregates directly link to AD pathogenesis, leading to synaptic dysfunction and cognitive decline. When amyloid beta precursor protein (APP) has mutations on the genetic level, patients are likely to have familial AD. In addition, the presenilin (PSEN) gene is another target gene for AD research. Unfortunately, the existing therapies are still ineffective as they can only delay AD progression but cannot stop nor reverse it. Recently, CRISPR-Cas9 has emerged as a promising gene-editing tool in AD research. CRISPR-Cas9 is an outstanding tool compared with the first two generations of gene editing techniques, as CRISPR-Cas9 is cheaper and more efficient. It can create desired mutations in precise positions to target gene sequences, thus potentially manipulating the genes related to familial AD. By mitigating the overproduction of Aβ and tau protein aggregates, researchers aim to slow down or halt the disease progression. CRISPR-Cas9 has significant potential in constructing AD models, screening AD pathogenic genes, and developing targeted therapies for AD. Such a technique offers scientists a better understanding of AD pathogenesis and enlightens more efficient genetic therapies. This review systematically illustrates the CRISPR-Cas9 system and further explains its implementation in AD model constructions, pathogenic genes searching, and potential treatment for AD.

Andrographolide derivative Andro-III modulates neuroinflammation and attenuates neuropathological changes of Alzheimer's disease via GSK-3β/NF-κB/CREB pathway

Andrographolide has anti-inflammatory and neuroprotective effects, making it a potential therapeutic option for Alzheimer's disease (AD). Our research group optimized its structure in a previous study to minimize the risk of renal toxicity, which would beneficial for future clinical research. This study aims to examine the impact of Andro-III on enhancing cognitive learning ability in 3xTg-AD mice, as well as the mechanisms involved. Andro-III improved spatial learning ability, prevented the loss of Nysted's vesicles, reduced the accumulation of β-amyloid (Aβ) and tau proteins, and suppressed microglial activation. Further research found that the expression of nuclear factor kappa-B RelA (NF-κB p65) expression and glycogen synthase kinase-3β (GSK-3β) activity were inhibited, while CREB was upregulated in brain tissue treated with Andro-III. Moreover, Andro-III downregulated the expression of IBA1 and inflammatory factors in microglial cells of mice induced by Aβ. The regulation of the GSK-3β/NF-κB/CREB pathway was similar to that observed in 3xTg-AD mice. Therefore, Andro-III modulates neuroinflammation and attenuates neuropathological changes of AD via the GSK-3β/NF-κB/CREB pathway.

Therapeutic effects of long-term HBOT on Alzheimer's disease neuropathologies and cognitive impairment in APPswe/PS1dE9 mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder with the pathological hallmarks of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. Although there is a hope that anti-amyloid monoclonal antibodies may emerge as a new therapy for AD, the high cost and side effect is a big concern. Non-drug therapy is attracting more attention and may provide a better resolution for the treatment of AD. Given the fact that hypoxia contributes to the pathogenesis of AD, hyperbaric oxygen therapy (HBOT) may be an effective intervention that can alleviate hypoxia and improve AD. However, it remains unclear whether long-term HBOT intervention in the early stage of AD can slow AD progression and ultimately prevent cognitive impairment in this disease. In this study we applied consecutive 3-month HBOT interventions on 3-month-old APPswe/PS1dE9 AD mice which represent the early stage of AD. When the APPswe/PS1dE9 mice at 9-month-old which represent the disease stage we measured cognitive function, 24-h blood oxygen saturation, Aβ and tau pathologies, vascular structure and function, and neuroinflammation in APPswe/PS1dE9 mice. Our results showed that long-term HBOT can attenuate the impairments in cognitive function observed in 9-month-old APPswe/PS1dE9 mice. Most importantly, HBOT effectively reduced the progression of Aβ plaques deposition, hyperphosphorylated tau protein aggregation, and neuronal and synaptic degeneration in the AD mice. Further, long-term HBOT was able to enhance blood oxygen saturation level. Besides, long-term HBOT can improve vascular structure and function, and reduce neuroinflammation in AD mice. This study is the first to demonstrate that long-term HBOT intervention in the early stage of AD can attenuate cognitive impairment and AD-like pathologies. Overall, these findings highlight the potential of long-term HBOT as a disease-modifying approach for AD treatment.

Tau Secretion is Driven by Circadian Variations of Body Temperature during the Sleep/Wake Cycle: Implications for Tau Spreading in Alzheimer's Disease

Propagation of hyperphosphorylated and aggregated tau protein is a hallmark of Alzheimer’s disease (AD). Previously, we demonstrated that tau phosphorylation is inversely correlated with body temperature (BT) variations during the sleep/wake cycle. Tau is hyperphosphorylated during sleep (when BT is lower), compared to wakefulness (when BT is higher). Interestingly, it has been shown that tau in ISF and CSF is increased during wakefulness, suggesting increased secretion. We thus hypothesized that tau secretion might be regulated by BT during the sleep/wake cycle.

Serotonin receptors - a potential target for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, having an increasing impact on aging societies. It is known that the serotonin (5-HT) system of the brain, in addition to its critical role in the control of various physiological functions and behaviors, is involved in the regulation of migration, proliferation, differentiation, maturation and programmed death of neurons. At the same time, increasing evidence indicates the involvement of 5-HT neurotransmission in the mechanisms underlying the formation of insoluble aggregates of β-amyloid and tau protein, which are the main histopathological signs of AD. In this review, we focused our attention on the available data on the participation of various 5-HT receptors and the intracellular signaling cascades induced by them in pathological processes leading to the development of AD. First of all, this concerns information about the involvement of 5-HT receptors in the mechanisms of protein aggregation in AD, which indicate that specific changes in the function of certain 5-HT receptors or associated intracellular signal transduction mediators prevent the accumulation of β-amyloid plaques and neurofibrillary tau protein tangles. Based on the accumulated experimental data, it can be assumed that the use of 5-HT receptors as new drug targets may not only be useful for improving cognitive performance in AD, but will also play an important role in treating the causes of AD-related dementia.

Atomic insights into the inhibition of R3 domain of tau protein by epigallocatechin gallate, quercetin and gallic acid

Inhibiting tau protein aggregation has become a prospective avenue for the therapeutic development of tauopathies. The third microtubule-binding repeat (R3) domain of tau is confirmed as the most aggregation-favorable fragment of the whole protein. As dimerization is the first step of the aggregation of tau into amyloid fibrils, impeding the dimerization of the R3 domain is critical to prevent the full-length tau aggregation. Natural polyphenol small molecules epigallocatechin gallate (EGCG), quercetin (QE) and gallic acid (GA) are proven to inhibit the aggregation of the full-length recombinant tau (For EGCG and QE) or the R3 domain (For GA) of tau in vitro. However, the underlying molecular mechanisms of the inhibitive effects on the R3 domain of tau remain largely unknown. In this study, we conducted numerous all-atom molecular dynamics simulations on R3 dimers with and without EGCG, QE or GA, respectively. The results reveal that all three molecules can effectively decrease the β structure composition of the R3 dimer, induce the dimer to adopt loosely-packed conformations, and weaken interchain interactions, thus impeding the dimerization of the R3 peptide chains. The specific preferentially binding sites for the three molecules exhibit similarities and differences. Hydrophobic, π-π stacking and hydrogen-bonding interactions collectively drive EGCG, QE and GA respectively binding on the R3 dimer, while QE also binds with the dimer through cation-π interaction. Given the incurable nature of tauopathies hitherto, our research provides helpful knowledge for the development of drugs to treat tauopathies.

Calcineurin inhibition prevents hippocampal synaptic plasticity impairment induced by brain‐derived tau oligomers via modulation of the transcriptome

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) strongly correlates with tau protein accumulation, with the most toxic species being in form of oligomers [1,2]. Due to the polymorphism of tau oligomers, isolating and testing brain‐derived tau oligomers (BDTO) directly from AD patients could provide new insights into tau toxicity. BDTO are potent inhibitors of long‐term potentiation (LTP) in hippocampal brain slices [3], however the involved mechanism is still not fully understood. We previously reported significantly reduced incidence of AD in aging humans chronically treated with a FDA‐approved calcineurin inhibitor, FK506, used as immunosuppressant after solid organ transplant [4]. Here we show that impairment of the synaptic functionality driven by BDTO is restored by calcineurin inhibition using FK506 via selective transcriptomic changes.MethodCombination of electrophysiological and RNA‐seq techniques were used. Ex‐vivo slices from 8‐12 weeks old C67BL/6J mice were treated with aCSF (Ctrl), BDTO (100nM) or BDTO+FK506. Field excitatory post‐synaptic potentials (fEPSPs) recordings were performed by stimulating the Schaffer collateral pathway, and recording electrode was located at the junction of the alveus and cornu ammonius 1 (CA1). After electrophysiological recordings, the hippocampus was isolated from the brain slice, snap frozen and processed for RNA‐seq.ResultFK506 treatment significantly ameliorated the BDTO‐induced attenuation of fEPSP. One‐way ANOVA followed by Tukey’s test, showed that BDTO caused reduction of fEPSP compared to Ctrl (p = 0.068). fEPSP was re‐established at physiological levels in the group BDTO+FK506 (vs Ctrl p = 0.603; vs BDTO p = 0.0163). A similar trend was observed when we analyzed the paired‐pulse ratio. Analysis of the transcriptome showed that FK506 modulates key synaptic transcripts impaired after BDTO treatment.ConclusionOur study provides evidence that FK506 has the potential to block the BDTO toxic effect on synaptic plasticity. These results suggest that FK506 may represent a promising therapeutic strategy for the treatment of AD. Further research is needed to elucidate the precise molecular mechanisms underlying FK506‐mediated neuroprotection and to explore its potential in in vivo models of AD.

Serotonin Receptors as a Potential Target in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide that has an increasing impact on aging societies. Besides its critical role in the control of various physiological functions and behavior, brain serotonin (5-HT) system is involved in the regulation of migration, proliferation, differentiation, maturation, and programmed death of neurons. At the same time, a growing body of evidence indicates the involvement of 5-HT neurotransmission in the formation of insoluble aggregates of β-amyloid and tau protein, the main histopathological signs of AD. The review describes the role of various 5-HT receptors and intracellular signaling cascades induced by them in the pathological processes leading to the development of AD, first of all, in protein aggregation. Changes in the functioning of certain types of 5-HT receptors or associated intracellular signaling mediators prevent accumulation of β-amyloid plaques and tau protein neurofibrillary tangles. Based on the experimental data, it can be suggested that the use of 5-HT receptors as new drug targets will not only improve cognitive performance in AD, but will be also important in treating the causes of AD-related dementia.

The Derivatives of Cromolyn Ameliorate the Abnormal Misfolding of Amyloid Proteins and Neuroinflammation in the Neural Cells.

The representative symptom of Alzheimer's Disease (AD) has mainly been mentioned to be misfolding of amyloid proteins, such as amyloid-beta (Aβ) and tau protein. In addition, the neurological pathology related to neuroinflammatory signaling has recently been raised as an important feature in AD. Currently, numerous drug candidates continue to be investigated to reduce symptoms of AD, including amyloid proteins misfolding and neuroinflammation. Our research aimed to identify the anti-AD effects of two chemical derivatives modified from cromoglicic acid, CNU 010 and CNU 011. CNU 010 and CNU 011 derived from cromoglicic acid were synthesized. The inhibitory effects of Aβ and tau were identified by thioflavin T assay. Moreover, western blots were conducted with derivates CNU 010 and CNU 011 to confirm the effects on inflammation. CNU 010 and CNU 011 significantly inhibited the aggregation of Aβ and tau proteins. Moreover, they reduced the expression levels of mitogen-activated protein (MAP) kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) signaling proteins, which are representative early inflammatory signaling markers. Also, the inhibitory effects on the lipopolysaccharide (LPS)-induced cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expression referring to late inflammation were confirmed. Our results showing multiple beneficial effects of cromolyn derivatives against abnormal aggregation of amyloid proteins and neuroinflammatory signaling provide evidence that CNU 010 and CNU 011 could be further developed as potential drug candidates for AD treatment.

Positron emission tomography (PET) imaging of neuroinflammation in healthy and Alzheimer disease participants using TSPO tracers

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. In addition to the widely recognized accumulation of amyloid and tau protein being the core pathology of AD, neuroinflammation is another cause of brain dysfunction and structural change. Expression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. With the development of TSPO positron emission tomography (PET) tracer, we were able to evaluate neuroinflammation non‐invasively in a clinical cohort of AD spectrum.MethodCognitively impaired patients (including AD and mild cognitive impairment (MCI)) and cognitively normal controls (CN) were recruited from single dementia clinic. [18F]FEPPA, the second‐generation PET ligand specifically binds TSPO was synthesized fully automated. Structural brain MRI and functional PET imaging were performed simultaneously with a PET/MR scanner (SIGNA, GE Company, USA). Kinetic analyses were performed using PMOD 4.2 modeling software. Total distribution volume (VT) in each ROI, including frontal, temporal, inferiolateral parietal, occipital, hippocampus and cerebellum, were derived from a two‐tissue compartment model (2‐TCM). In addition, APOE and rs6971 polymorphism genotyping were conducted in all subjects. Mann‐Whitney U Tet, Kruskal‐Wallis Test and linear correlation were performed.ResultA total of 39 participants (23 males and 16 females) participated, including 13 cognitively normal, 9 with MCI and 17 with Alzheimer’s disease. The rs6971 genotype had no significant effect on [18F]FEPPA binding to TSPO. The amount of TSPO expression was independent of age, gender, and APOE ε4 carrier status. The VT of each ROI did not differ significantly between cognitive groups. VT of frontal, temporal, inferiolateral parietal and occipital lobe were all negatively correlated with MMSE, Boston Naming Test and Trial Making A performance. However, such association was not observed between VT of hippocampus and cognitive tests.ConclusionAlthough there was no difference between TSPO expression in each ROI among cognitive groups, we still observed that higher TSPO expression in the cortex was associated with worse performance in certain cognitive tests. This implied that the increase in neuroinflammation was related to the decline of cognitive performance regardless of cognitive diagnosis.

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.

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

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