Neurofibrillary Tangles Research Articles

Dendrimers-Novel Therapeutic Approaches for Alzheimer's Disease.

Dendrimers are covalently bonded globular nanostructures that may be used in the treatment of Alzheimer's disease (AD). Nowadays, AD therapies are focused on improving cognitive functioning and not causal treatment. However, this may change with the use of dendrimers, which are being investigated as a drug-delivery system or as a drug per se. With their ability to inhibit amyloid formation and their anti-tau properties, they are a promising therapeutic option for AD patients. Studies have shown that dendrimers may inhibit amyloid formation in at least two ways: by blocking fibril growth and by breaking already existing fibrils. Neurofibrillary tangles (NFTs) are abnormal filaments built by tau proteins that can be accumulated in the cell, which leads to the loss of cytoskeletal microtubules and tubulin-associated proteins. Cationic phosphorus dendrimers, with their anti-tau properties, can induce the aggregation of tau into amorphous structures. Drug delivery to mitochondria is difficult due to poor transport across biological barriers, such as the inner mitochondrial membrane, which is highly negatively polarized. Dendrimers may be potential nanocarriers and increase mitochondria targeting. Another considered use of dendrimers in AD treatment is as a drug-delivery system, for example, carbamazepine (CBZ) or tacrine. They can also be used to transport siRNA into neuronal tissue and to carry antioxidants and anti-inflammatory drugs to act protectively on the nervous system.

Influence of Exercise and Genistein to Mitigate the Deleterious Effects of High-Fat High-Sugar Diet on Alzheimer's Disease-Related Markers in Male Mice.

The prevalence of obesity and related consequences, including insulin resistance and Alzheimer's-like neuropathology, has increased dramatically. Contributing to this prevalence is the shift in lifestyle preference away from wholesome foods and exercise to the Western-style diet and sedentarism. Despite advances in drug development, a healthy diet and regular exercise remain the most effective approaches to mitigating the unwanted sequelae of diet-induced obesity on brain health. In this study, we used the high-fat high-sugar (HFHS) mouse model of neurodegeneration to examine the effects of exercise training (HFHS+Ex), genistein treatment (HFHS+Gen), and combination treatment (HFHS+Ex+Gen) on proteins relating to neurodegeneration in the brain of male mice. After a period of 12 weeks, as expected, HFHS feeding increased body weight, adipose tissue weight, and systemic plasma inflammation (TNF-α) compared to lean mice fed a standard diet. HFHS feeding also increased protein expression of brain markers of insulin resistance (pGSK-3β, p-IR), apoptosis (caspase 3), early neurofibrillary tangles (CP13), and amyloid-beta precursor (CT20). Compared to HFHS mice, Ex decreased body weight, plasma TNF-α, and expression of pGSK-3β, caspase 3, CP13, amyloid-β precursor (22c11), and ADAM10. Treatment with Gen was equally protective on these markers and decreased the expression of p-IR. Combination treatment with Ex and Gen afforded the greatest overall benefits, and this group exhibited the greatest reduction in body and adipose tissue weight and all brain markers, except for 22c11 and ADAM10, which were decreased compared to mice fed an HFHS diet. In addition, levels of 4G8, which detects protein levels of amyloid-β, were decreased with combination treatment. Our results indicate that exercise training, genistein supplementation, or combination treatment provide varying degrees of neuroprotection from HFHS feeding-induced Alzheimer's pathology. Future perspectives could include evaluating moderate exercise regimens in combination with dietary supplementation with genistein in humans to determine whether the same benefits translate clinically.

Iron Chelators and Alzheimer's Disease Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-β (Aβ) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aβ plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research.

Improving Cognition Without Clearing Amyloid: Effects of Tau and Ultrasound Neuromodulation.

Alzheimer's disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature of dementia is protein aggregation, a process by which a monomer forms intermediate oligomeric assembly states and filaments that develop into end-stage hallmark lesions. In Alzheimer's disease, this is exemplified by extracellular amyloid-β (Aβ) plaques which have been placed upstream of tau, found in intracellular neurofibrillary tangles and dystrophic neurites. This implies causality that can be modeled as a linear activation cascade. When Aβ load is reduced, for example, in response to an anti-Aβ immunotherapy, cognitive functions improve in plaque-forming mice. They also deteriorate less in clinical trial cohorts although real-world clinical benefits remain to be demonstrated. Given the existence of aged humans with unimpaired cognition despite a high plaque load, the central role of Aβ has been challenged. A counter argument has been that clinical symptoms would eventually develop if these aged individuals were to live long enough. Alternatively, intrinsic mechanisms that protect the brain in the presence of pathology may exist. In fact, Aβ toxicity can be abolished by either reducing or manipulating tau (through which Aβ signals), at least in preclinical models. In addition to manipulating steps in this linear pathocascade model, mechanisms of restoring brain reserve can also counteract Aβ toxicity. Low-intensity ultrasound is a neuromodulatory modality that can improve cognitive functions in Aβ-depositing mice without the need for removing Aβ. Together, this highlights a dissociation of Aβ and cognition, with important implications for therapeutic interventions.

Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases

The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer’s disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer’s disease (n = 17), primary tauopathies (n = 8), synucleinopathies (n = 27), frontotemporal lobar degeneration (n = 8), mixed pathology (n = 11), other neurodegenerative diseases (n = 6), and cognitively normal controls (n = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer’s disease, primary tauopathies and controls with Alzheimer’s disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (n = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (n = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (n = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (n = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates associated with the main neurodegenerative disease. These findings indicate that with appropriate retinal imaging techniques, retinal biomarkers have the potential to become highly accurate indicators for diagnosing the major neurodegenerative diseases of the brain.

Associations between Brain Alpha-Tocopherol Stereoisomer Profile and Hallmarks of Brain Aging in Centenarians.

Brain alpha-tocopherol (αT) concentration was previously reported to be inversely associated with neurofibrillary tangle (NFT) counts in specific brain structures from centenarians. However, the contribution of natural or synthetic αT stereoisomers to this relationship is unknown. In this study, αT stereoisomers were quantified in the temporal cortex (TC) of 47 centenarians in the Georgia Centenarian Study (age: 102.2 ± 2.5 years, BMI: 22.1 ± 3.9 kg/m2) and then correlated with amyloid plaques (diffuse and neuritic plaques; DPs, NPs) and NFTs in seven brain regions. The natural stereoisomer, RRR-αT, was the primary stereoisomer in all subjects, accounting for >50% of total αT in all but five subjects. %RRR was inversely correlated with DPs in the frontal cortex (FC) (ρ = -0.35, p = 0.032) and TC (ρ = -0.34, p = 0.038). %RSS (a synthetic αT stereoisomer) was positively correlated with DPs in the TC (ρ = 0.39, p = 0.017) and with NFTs in the FC (ρ = 0.37, p = 0.024), TC (ρ = 0.42, p = 0.009), and amygdala (ρ = 0.43, p = 0.008) after controlling for covariates. Neither RRR- nor RSS-αT were associated with premortem global cognition. Even with the narrow and normal range of BMIs, BMI was correlated with %RRR-αT (ρ = 0.34, p = 0.021) and %RSS-αT (ρ = -0.45, p = 0.002). These results providing the first characterization of TC αT stereoisomer profiles in centenarians suggest that DP and NFT counts, but not premortem global cognition, are influenced by the brain accumulation of specific αT stereoisomers. Further study is needed to confirm these findings and to determine the potential role of BMI in mediating this relationship.

Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.

Relationships between regional burden of tau pathology and age at death and disease duration in PSP

BackgroundA definitive diagnosis of progressive supranuclear palsy (PSP) can only be established through neuropathological evaluations where four cardinal tau lesions are identified. Relationships between regional tau burden and disease duration/age at death is unclear. ObjectiveTo investigate relationships between tau burden in different brain regions and disease duration and age at death in PSP and determine whether association are influenced by PSP subtype (subcortical/cortical) or co-pathologies. MethodsWe identified 45 patients with definite PSP who were evaluated at Mayo Clinic between 2009 and 2023, died and underwent histopathological evaluation. We performed semi-quantitative lesion count for each of four cardinal lesions (pretangles/globose neurofibrillary tangles, threads, tufted astrocytes, and coiled bodies) across 10 brain regions. We fit Bayesian linear hierarchical regression models to estimate the relationship between total pathological burden, and disease duration and age at death by region and the influence of subtype and co-pathologies. ResultsOf the 45 patients, 18 (40 %) were female. Median age at death was 75 (56–87) years and median disease duration was 8 (3,15) years. Younger age at death was associated with greater total tau burden in the pallidum, red nucleus, striatum, and subthalamic nucleus (all p ≤ 0.01). Shorter disease duration was associated with greater total tau burden in the red nucleus (p = 0.05). There was no evidence for a difference in association between lesion types. PSP subtype and co-pathologies did not influence associations. ConclusionsThe findings from this study suggest that age and disease duration influence burden of tau pathology in subcortical regions in PSP.

Loss of DNA glycosylases improves health and cognitive function in a C. elegans model of human tauopathy.

Alzheimer's disease (AD) is a neurodegenerative disorder representing a major burden on families and society. Some of the main pathological hallmarks of AD are the accumulation of amyloid plaques (Aβ) and tau neurofibrillary tangles. However, it is still unclear how Aβ and tau aggregates promote specific phenotypic outcomes and lead to excessive oxidative DNA damage, neuronal cell death and eventually to loss of memory. Here we utilized a Caenorhabditis elegans (C. elegans)model of human tauopathy to investigate the role of DNA glycosylases in disease development and progression. Transgenic nematodes expressing a pro-aggregate form of tau displayed altered mitochondrial content, decreased lifespan, and cognitive dysfunction. Genetic ablation of either of the two DNA glycosylases found in C. elegans, NTH-1 and UNG-1, improved mitochondrial function, lifespan, and memory impairment. NTH-1 depletion resulted in a dramatic increase of differentially expressed genes, which was not apparent in UNG-1 deficient nematodes. Our findings clearly show that in addition to its enzymatic activity, NTH-1 has non-canonical functions highlighting its modulation as a potential therapeutic intervention to tackle tau-mediated pathology.

Astrocytic centrin-2 expression in entorhinal cortex correlates with Alzheimer's disease severity.

Astrogliosis is a condition shared by acute and chronic neurological diseases and includes morphological, proteomic, and functional rearrangements of astroglia. In Alzheimer's disease (AD), reactive astrocytes frame amyloid deposits and exhibit structural changes associated with the overexpression of specific proteins, mostly belonging to intermediate filaments. At a functional level, amyloid beta triggers dysfunctional calcium signaling in astrocytes, which contributes to the maintenance of chronic neuroinflammation. Therefore, the identification of intracellular players that participate in astrocyte calcium signaling can help unveil the mechanisms underlying astrocyte reactivity and loss of function in AD. We have recently identified the calcium-binding protein centrin-2 (CETN2) as a novel astrocyte marker in the human brain and, in order to determine whether astrocytic CETN2 expression and distribution could be affected by neurodegenerative conditions, we examined its pattern in control and sporadic AD patients. By immunoblot, immunohistochemistry, and targeted-mass spectrometry, we report a positive correlation between entorhinal CETN2 immunoreactivity and neurocognitive impairment, along with the abundance of amyloid depositions and neurofibrillary tangles, thus highlighting a linear relationship between CETN2 expression and AD progression. CETN2-positive astrocytes were dispersed in the entorhinal cortex with a clustered pattern and colocalized with reactive glia markers STAT3, NFATc3, and YKL-40, indicating a human-specific role in AD-induced astrogliosis. Collectively, our data provide the first evidence that CETN2 is part of the astrocytic calcium toolkit undergoing rearrangements in AD and adds CETN2 to the list of proteins that could play a role in disease evolution.

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

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

Cryo-EM structures of cotton wool plaques’ amyloid β and of tau filaments in dominantly inherited Alzheimer disease

Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.

A pentavalent peptide vaccine elicits Aβ and tau antibodies with prophylactic activity in an Alzheimer’s disease mouse model

Amyloid-β (Aβ) and hyperphosphorylated tau protein are targets for Alzheimer’s Disease (AD) immunotherapies, which are generally focused on single epitopes within Aβ or tau. However, due to the complexity of both Aβ and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aβ peptides (1–14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404). These correspond to both soluble and aggregated targets and are displayed on the surface of immunogenic liposomes in an orientation that maintains reactivity with epitope-specific monoclonal antibodies. Intramuscular immunization of mice with individual epitopes resulted in minimally cross-reactive antibody induction, while simultaneous co-display of 5 antigens (“5-plex”) induced antibodies against all epitopes without immune interference. Post-immune sera recognized plaques and neurofibrillary tangles from human AD brain tissue. Vaccine administration to 3xTg-AD mice using a prophylactic dosing schedule inhibited tau and amyloid pathologies and resulted in improved cognitive function. Immunization was well tolerated and did not induce antigen-specific cellular responses or persistent inflammatory responses in the peripheral or central nervous system. Antibody levels could be reversed by halting monthly vaccinations. Altogether, these results indicate that active immune therapies based on nanoparticle formulations of multiple Aβ and tau epitopes warrant further study for treating early-stage AD.

Characteristics of streptozotocin-induced and okadaic acid-induced models of Alzheimer's disease

alzheimer's disease is the main cause of dementia in people over the age of 65, which affects millions of patients worldwide. Since the prevalence of this pathology increases significantly with the increase in life expectancy, the societal consequences of Alzheimer's disease will be dire if no effective therapy is developed in the near future. Fundamental experimental work is a mandatory and necessary stage of preclinical research for the safe and effective development of new approaches to the treatment of dementia as part of clinical trials in the future. Streptozotocin is a natural chemical obtained from Streptomyces achromogenes, primarily classified as an antibiotic, the introduction of which leads to the activation of oxidative stress and damage to the myelin sheath. This chemical compound promotes the accumulation of characteristic abnormal proteins, called β-amyloid and tau protein, which leads to imitation of neuropathological, behavioral, metabolic and molecular symptoms that resemble human Alzheimer's disease. Okadaic acid is a C38 fatty acid polyester phycotoxin, which is a powerful and selective inhibitor of serine/threonine phosphatases: PP-1c, PP1, PP2A and PP2B, which leads to a decrease in dephosphorylation of phosphorylated tau protein and, accordingly, to hyperphosphorylation of tau protein. Hyperphosphorylation of tau protein is responsible for the deposition of neurofibrillary tangles in vivo and in vitro, which ultimately causes synaptic dysfunction and neuronal death. In addition, okadaic acid activates kinases that regulate tau protein phosphorylation: GSK3β, CDK5, MAPK, ERK1/2, AMPK. The activation of kinases significantly contributes to the phosphorylation of tau protein. Okadain administration is also reported to significantly activate the expression of BACE1, one of the key enzymes in the amyloidogenic cascade. The mechanisms of molecular and morphological changes of the Alzheimer's type in the brain of experimental animals when streptozotocin and okadaic acid are administered are similar in many respects. These include induction and activation of neurodegeneration, apoptosis and necrosis of neurons, development of oxidative stress and inhibition of antioxidant systems, deficiency of neurotransmitters and mitochondrial dysfunction, etc. Both proposed toxins effectively contribute to the simulation of dementia of the Alzheimer's type in the experiment.

Anthocyanin-Rich Fraction of Black Rice Bran Extract Protects against Amyloid β-Induced Oxidative Stress, Endoplasmic Reticulum Stress, and Neuronal Apoptosis in SK-N-SH Cells.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the aging population. An accumulation of amyloid plaques and neurofibrillary tangles causes degeneration of neurons, leading to neuronal cell death. The anthocyanin-rich fraction of black rice (Oryza sativa L. variety "Luem Pua") bran (AFBRB), extracted using a solution of ethanol and water and fractionated using Amberlite XAD7HP column chromatography, contains a high anthocyanin content (585 mg of cyanidin-3-O-glucoside and 24 mg of peonidin-3-O-glucoside per gram of the rich extract), which has been found to reduce neurodegeneration. This study focused on the neuroprotective effects of AFBRB in Aβ25-35-induced toxicity in the human neuroblastoma cell line (SK-N-SH). SK-N-SH was exposed to Aβ25-35 (10 µM) to induce an AD cell model in vitro. Pretreatment with AFBRB (0.1, 1, or 10 µg/mL) or C3G (20 µM) was conducted for 2 h prior to the treatment with Aβ25-35 (10 µM) for an additional 24 h. The results indicate that AFBRB can protect against the cytotoxic effect of Aβ25-35 through attenuation of intracellular ROS production, downregulation of the expression of the proteins Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3, upregulation of the expression of Bcl-2 in the mitochondrial death pathway, and reduction in the expression of the three major markers of ER stress pathways in similar ways. Interestingly, we found that pretreatment with AFBRB significantly alleviated Aβ-induced oxidative stress, ER stress, and apoptosis in SK-N-SH cells. This suggests that AFBRB might be a potential therapeutic agent in preventing neurodegenerative diseases.

Ligand-Based Virtual Screening as a Path to New Chemotypes for Candidate PET Radioligands for Imaging Tauopathies.

Ligand-based virtual screening (LBVS) has rarely been tested as a method for discovering new structural scaffolds for PET radioligand development. This study used LBVS to discover potential chemotype leads for developing radioligands for PET imaging of tauopathies. ZINC12, a free database of over 12 million commercially available compounds, was searched to discover novel scaffolds based on similarities to four query compounds. Thirteen high-ranking hits were purchased and assayed for their ability to compete against three tritiated radioligands at their distinct binding sites in Alzheimer's disease brain tissue. Three hits were 2-substituted 6-methoxy naphthalenes. Synthetic elaboration of this new chemotype yielded three new ligands (25, 26, and 28) with high affinity for the [3H]6 (flortaucipur) neurofibrillary tangle binding site. Compound 28 showed remarkably high affinity (Ki, 7 nM) and other desirable properties for a candidate PET radioligand, including low topological polar surface area, moderate computed log D, and amenability for labeling with carbon-11. LBVS appears to be uniquely valuable for discovering new chemotypes for candidate PET radioligands.

Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease

Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.

Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease

Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Aβ) and Tau proteins, neuroinflammation, metabolic changes and neuronal death. Reactive astrocytes participate in these pathophysiological processes by releasing pro-inflammatory molecules and recruiting the immune system, which further reinforces inflammation and contributes to neuronal death. Besides these neurotoxic effects, astrocytes can protect neurons by providing them with high amounts of lactate as energy fuel. Astrocytes rely on aerobic glycolysis to generate lactate by reducing pyruvate, the end product of glycolysis, through lactate dehydrogenase. Consequently, limited amounts of pyruvate enter astrocytic mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to be oxidized. The MPC is a heterodimer composed of two subunits MPC1 and MPC2, the function of which in astrocytes has been poorly investigated. Here, we analyzed the role of the MPC in the pathogeny of AD, knowing that a reduction in overall glucose metabolism has been associated with a drop in cognitive performances and an accumulation of Aβ and Tau. We generated 3xTgAD mice in which MPC1 was knocked-out in astrocytes specifically and focused our study on the biochemical hallmarks of the disease, mainly Aβ and neurofibrillary tangle production. We show that inhibition of the MPC before the onset of the disease significantly reduces the quantity of Aβ and Tau aggregates in the brain of 3xTgAD mice, suggesting that acting on astrocytic glucose metabolism early on could hinder the progression of the disease.

18F-THK5351 Uptake May Not Estimate Neurofibrillary Tangles in In Vivo Images: A Comparison With 18F-MK-6240 Uptake.

Currently, monoamine oxidase B is recognized as the primary target of 18F-THK5351, although 18F-THK5351 was initially developed to target neurofibrillary tangles (NFTs) in Alzheimer disease. When clinically applying 18F-THK5351 PET to visualize ongoing astrogliosis via estimating monoamine oxidase B levels, a crucial concern is how much degree 18F-THK5351 uptake reflects NFTs in in vivo images. To unravel this concern, a head-to-head comparison between 18F-THK5351 and 18F-MK-6240 (estimating NFT) images in the NFT lesion ideally without accompanying astrogliosis is essential. Here, we present such a case suggesting that 18F-THK5351 uptake may not estimate NFTs in in vivo images.

Outcome of resveratrol and resveratrol with donepezil combination on the β-amyloid plaques and neurofibrillary tangles in Alzheimer’s disease

The goal of this research was to study the effect of different doses of resveratrol (RS) and RS with donepezil (DPZ) on the deposition of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) in colchicine-induced Alzheimer’s disease (AD) brain. The study included three months old male Albino Wistar rats and consisted of six animal groups: AD model (group 1), treatment groups, RS 10 mg/kg body weight (group 2), RS 20 mg/kg body weight (group 3), RS 10 mg/kg body weight along with DPZ 1 mg/kg body weight (group 6), prophylaxis groups, RS 10 mg/kg body weight (group 4) and RS 20 mg/kg body weight (group 5). In the treatment groups, RS was given for 7 consecutive days from the day of induction of AD, and in the prophylaxis groups, we started RS 7 days even before the induction of AD and continued for seven days after the induction. The number of Aβs and NFTs at the frontal region, cornu ammonis (CA) 1,2,3,4 and dentate gyrus regions of hippocampus were evaluated. The immunohistochemical analysis was performed by using mouse anti-β-amyloid antibody for the Aβ plaques and polyclonal rabbit anti-human tau for the tau-positive neurons. The present study observed the accumulation of Aβ plaques and tau-positive neurons in the AD model. However, their numbers were significantly decreased in the treatment groups (p < 0.001). The best results were observed when RS 10 mg was given prophylactically (p < 0.01) and RS along with DPZ (p < 0.001), suggesting the neuroprotective effect of RS and its synergistic effect with the DPZ.