Abnormal Hyperphosphorylation Of Tau Research Articles

P. GINGIVALIS–LPS-INDUCED NLRP3 INFLAMMASOME ACTIVATION DRIVES AD PATHOLOGIES

Abstract Alzheimer’s disease (AD) is the leading cause of dementia among older adults. AD is characterized by amyloid-β deposition, abnormal hyperphosphorylation of tau leading to the formation of neurofibrillary tangles, and neuroinflammation. Porphyromonas gingivalis, the keystone-pathogen of periodontitis, is being increasingly linked with AD and Alzheimer’s disease-related dementias (ADRD). Poor oral health is common in older populations, and literature suggests that oral health correlates with prevalence of ADRD. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated IL-1β is significantly involved in periodontal diseases. However, the exact mechanism by which NLRP3 inflammasome is regulated in response to pathogenic bacteria remains unclear. We hypothesized that P. gingivalis-LPS may be responsible for the neuroinflammation via TLR4 activation and its downstream caspase-1, caspase-3 or caspase-4/5/11 dependent cell signaling. Our results suggest that P. gingivalis accelerated the induction of NLRP3. Furthermore, NLRP3/Caspase-1/Caspase-4/5/11 dependent IL-1β production may contribute to the dysregulated neuroinflammatory response in AD pathogenesis.

Increasing O-GlcNAcylation Attenuates tau Hyperphosphorylation and Behavioral Impairment in rTg4510 Tauopathy Mice.

Tauopathies such as Alzheimer's disease (AD) are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau (MAPT) aggregating into neurofibrillary tangles (NFTs). O-linked β-N-acetylglucosamine (O-GlcNAc) modifications have been suggested to regulate tau phosphorylation and aggregation and N-acetylglucosaminidase (OGA) removes GlcNAc moieties from proteins. We investigated effects of the OGA inhibitor Thiamet G in rTg4510 primary neuronal cultures and in rTg4510 mice. The rTg4510 mice overexpress human tau harboring the P301L mutation and display an age-dependent progression of tau pathology including hyperphosphorylated tau species and NFTs. Aged rTg4510 mice exhibit a non-mnemonic behavioral defect involving a hyperactive phenotype that is associated with the progression of tau pathology. Thiamet G increased overall O-GlcNAc levels and crossed the blood brain barrier in rTg4510 mice. The free fraction of Thiamet G in the brain was 22-fold above the half maximal effective concentration (EC50) measured in rTg4510 primary neurons. Chronic Thiamet G treatment (18 weeks) initiated in young 6 week old rTg4510 mice increased brain O-GlcNAc levels and this corresponded with a significant reduction in soluble and insoluble hyperphosphorylated tau in aged 24 week old rTg4510 mice. Levels of normally phosphorylated P301L tau were not altered under these conditions. Reduction of hyperphosphorylated tau species by increased O-GlcNAcylation was associated with significant attenuation of hyperactivity in 24 week old rTg4510 mice. Our findings support the pharmacological inhibition of OGA as a potential therapeutic approach for the treatment of AD and other tauopathies.

ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein.

Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between theER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism.

A peptide rich in glycine-serine-alanine repeats ameliorates Alzheimer-type neurodegeneration.

Repeated amino acid sequences in proteins are widely found, and the glycine-serine-alanine repeat is an element with a general propensity to form β-sheet aggregates as found in key pathological factors, in several neurodegenerative diseases. Such properties of this repeat may guide development of disease-modifying therapies for neurodegenerative disease. However, details of its role and underlying mechanism(s) remain largely unknown. Actions of specific glycine-serine-alanine repeat peptides (SNPs), especially SNP-9, on Alzheimer's disease (AD)-like abnormalities were evaluated in transgenic mice and Caenorhabditis elegans, andin rat and cell models. Entry of SNPs into the brain, SNP activity in neuronal cells and peptide entry into cells were analysed in vivo and in vitro. Cell-free systems and the yeast two-hybrid system were also used to explore possible targets of SNP-9, and interactions of potential targets with SNP-9 were confirmed in cell-based systems. We first identified SNP-9 as a potent neuroprotective peptide with the activity to decrease oligomeric amyloid β (Aβ) via co-assembling with the toxic Aβ oligomer to form hetero-oligomers. Also, calcyclin-binding protein was found to act as a SNP-9-binding protein, by screening of a human brain cDNA library. Such binding showed that SNP-9 could regulate the abnormal hyperphosphorylation of tau via calcyclin-bindingprotein. Our study provides a foundation for development of SNPs, especially SNP-9, as potential therapeutic interventions for AD. We propose SNP-9 as a potential therapeutic agent for the treatment of AD.

Abnormal Hyperphosphorylation of Tau in Canine Immune-mediated Meningoencephalitis.

Tau is a microtubule-associated protein involved in the assembly and stabilization of microtubules. In human medicine, hyperphosphorylation of tau is associated with microtubule instability and is considered to play a role in the progression of multiple sclerosis (MS). MS is an autoimmune neurological disease that shares many characteristics, including pathological mechanisms, with canine meningoencephalitis of unknown etiology (MUE). With this background, this study investigated the presence of hyperphosphorylated tau in dogs with MUE and experimental autoimmune encephalomyelitis (EAE). In total, eight brain samples were examined from two neurologically normal dogs, three dogs with MUE, and three canine EAE models. Anti-(phospho-S396) tau antibody was used for immunohisto-chemistry, which stained hyperphosphorylated tau. In normal brain tissues, hyperphosphorylated tau was not found. In all the dogs with EAE and one of the dogs with MUE, immunoreactivity for S396 p-tau was observed in glial cell cytoplasm and the background in the periphery of the inflammatory lesion. These results suggest for the first time that tau pathology may be involved in the progression of neuroinflammation in dogs, similar to that in human MS.

Artificial intelligence-derived neurofibrillary tangle burden is associated with antemortem cognitive impairment

Tauopathies are a category of neurodegenerative diseases characterized by the presence of abnormal tau protein-containing neurofibrillary tangles (NFTs). NFTs are universally observed in aging, occurring with or without the concomitant accumulation of amyloid-beta peptide (Aβ) in plaques that typifies Alzheimer disease (AD), the most common tauopathy. Primary age-related tauopathy (PART) is an Aβ-independent process that affects the medial temporal lobe in both cognitively normal and impaired subjects. Determinants of symptomology in subjects with PART are poorly understood and require clinicopathologic correlation; however, classical approaches to staging tau pathology have limited quantitative reproducibility. As such, there is a critical need for unbiased methods to quantitatively analyze tau pathology on the histological level. Artificial intelligence (AI)-based convolutional neural networks (CNNs) generate highly accurate and precise computer vision assessments of digitized pathology slides, yielding novel histology metrics at scale. Here, we performed a retrospective autopsy study of a large cohort (n = 706) of human post-mortem brain tissues from normal and cognitively impaired elderly individuals with mild or no Aβ plaques (average age of death of 83.1 yr, range 55–110). We utilized a CNN trained to segment NFTs on hippocampus sections immunohistochemically stained with antisera recognizing abnormal hyperphosphorylated tau (p-tau), which yielded metrics of regional NFT counts, NFT positive pixel density, as well as a novel graph-theory based metric measuring the spatial distribution of NFTs. We found that several AI-derived NFT metrics significantly predicted the presence of cognitive impairment in both the hippocampus proper and entorhinal cortex (p < 0.0001). When controlling for age, AI-derived NFT counts still significantly predicted the presence of cognitive impairment (p = 0.04 in the entorhinal cortex; p = 0.04 overall). In contrast, Braak stage did not predict cognitive impairment in either age-adjusted or unadjusted models. These findings support the hypothesis that NFT burden correlates with cognitive impairment in PART. Furthermore, our analysis strongly suggests that AI-derived metrics of tau pathology provide a powerful tool that can deepen our understanding of the role of neurofibrillary degeneration in cognitive impairment.

Allantoin ameliorates amyloid β-peptide-induced memory impairment by regulating the PI3K/Akt/GSK-3β signaling pathway in rats

Alzheimer's disease (AD) is a brain disease that causes problems in memory, thinking, and behavior. Allantoin has been shown to have antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we aimed to investigate the effect and mechanism of action of allantoin on AD-related memory impairment. We investigated the effect of allantoin on an amyloid β1–42 peptide (Aβ1–42)-induced AD model in rats and evaluated its memory-enhancing effect using the Morris water maze test. Pathological changes in the hippocampus and cortex were examined by hematoxylin-eosin staining. The expression of the phosphorylated Tau protein and PI3K/Akt/GSK-3β signaling pathway was analyzed by western blotting. The results of the water maze test showed that after treatment with allantoin, the rats could reduce their swimming time and travel distances to find the platform. Allantoin treatment also increased the time spent in the quadrant in which the platform was located. Histological assessment showed that Aβ1–42 could cause morphological alterations in nerve cells in the hippocampal CA1 region, and that allantoin could repair the damage to these cells. Western blotting revealed that allantoin treatment increased the expression of p-PI3K, p-Akt, and p-GSK-3β and decreased p-Tau in the hippocampus and cortex of rats. These effects were inhibited by LY294002. These findings showed that allantoin could improve cognitive impairment in Aβ1–42-induced rats by activating the PI3K/Akt/GSK-3β signaling pathway to reduce abnormal hyperphosphorylation of Tau. Thus, allantoin may be a potential therapeutic agent for neurodegenerative diseases.

Low Glucose Induced Alzheimer’s Disease Phenotype in Induced Pluripotent Stem Cell‐Derived Neurons is Due to Decreased O‐GlcNAcylation

Sporadic Alzheimer’s disease (sAD) is the most common type of neurodegenerative disease. Recent studies show that detectable impairment of brain glucose metabolism occurs years before onset of AD symptoms, and the dysregulated O‐GlcNAc levels likely arisen from impaired glucose metabolism correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model. We have established a human sAD model in which the pathological features are reproduced by glucose deficiency that better represents sAD as a metabolic disease. We generated human cortical neurons from human induced pluripotent stem cell and treated mature neuron with glucose reduction media to study the effect of low glucose on the degenerative status of neuron. Fluoro JADE C staining and cell viability assays reveals low glucose treatment at 2mM leads to dramatic increases of degeneration cell on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, western blotting and immunofluorescent staining results demonstrate that long‐term low glucose treatment induces two major AD features in cortical neuron, including accumulation of abnormal hyperphosphorylated tau and increasing amyloid beta production. In addition, glucose deficiency also causes decreased neurite coverage, synapse loss, and neuron network activity disruption detected by immunofluorescent staining and multi‐electrode array electrophysiological analyses. Furthermore, we find that O‐GlcNAc levels are significantly reduced soon after low glucose treatment and last till the end of experiment. Artificially increasing O‐GlcNAc level by thiamet‐G (TMG) in low glucose treated neurons, rescues low glucose‐induced AD phenotypes. Moreover, our data show that O‐GlcNAc dysregulation results in mitochondrial dysfunction, which occurs before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis. Taken together, we established a human sAD model that mimics the main features of AD pathogenesis, which agrees with clinical observations of sAD patients. Therefore, this platform can serve as a tool to better understand molecular processes involved in sAD. Our results also suggest that dysregulated O‐GlcNAc levels by glucose deficiency is involved in the onset and progression of sAD.

Beneficial effects of levetiracetam in streptozotocin-induced rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. In the light of increasing AD prevalence and lack of effective treatment, new strategies to prevent or reverse this condition are needed. Levetiracetam (LEV) is a newer antiepileptic drug that is commonly used to treat certain types of seizures. Researches indicated that LEV has several other pharmacological activities, including improvement of cognitive function. In this study, the recovery effects of chronic (28 days) administration of LEV (50, 100, and 150mg/kg, ip) on cognitive deficits caused by the intracerebroventricular (icv) injection of streptozotocin (STZ), as a model for sporadic AD, were evaluated in rats. We also considered the protective effects of LEV against hippocampal cell loss, oxidative damage, acetylcholinesterase (AChE) activity, neuroinflammation, and tauopathy caused by STZ. LEV (100 and 150mg/kg) significantly attenuated the STZ-induced learning and memory impairments in the passive avoidance and Morris water maze (MWM) tasks. In addition, LEV suppressed STZ-induced hippocampal neuronal loss, while restored alterations in the redox status (lipid peroxides and glutathione), AChE activity, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and hyperphosphorylation of tau linked to STZ administration. In conclusion, our study demonstrated that LEV alleviated hippocampal cell death and memory deficits in STZ-AD rats, through mitigating oxidative damage, suppression of proinflammatory cytokines expression, and inhibition of abnormal tau hyperphosphorylation.

Ferroptosis promotes microtubule-associated protein tau aggregation via GSK-3β activation and proteasome inhibition.

Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. Iron dyshomeostasis and peroxidation damage of neurons in some particular brain regions are closely related to a wide range of neurodegenerative diseases known as "tauopathies," in which intracellular aggregation of microtubule-associated protein tau is the common neuropathological feature. However, the relationship between ferroptosis and tau aggregation is not well understood. The current study demonstrates that erastin-induced ferroptosis can promote tau hyperphosphorylation and aggregation in mouse neuroblastoma cells (N2a cells). Moreover, ferroptosis inhibitor ferrostatin-1 can alleviate tau aggregation effectively. In-depth mechanism research indicates that activated glycogen synthase kinase-3β (GSK-3β) is responsible for the abnormal hyperphosphorylation of tau. More importantly, proteasome inhibition can exacerbate tau degradation obstacle and accelerate tau aggregation in the process of ferroptosis. Our results indicate that ferroptosis can lead to abnormal aggregation of tau protein and might be a promising therapeutic target of tauopathies.

Porphyromonas Gingivalis in the Pathogenesis of Alzheimer’s Disease and Its Therapeutic Target

The leading cause of dementia is Alzheimer’s disease (AD), which affects millions worldwide. Aging populations can foretell the worsening burden of the disease in the future. AD is characterised by the following hallmark pathologies: amyloid-β over-production and deposition, abnormal hyperphosphorylation of tau leading to the formation of neurofibrillary tangles, and neuroinflammation. Many potential treatments fail in clinical trials, suggesting that present theories are outdated or lead to therapeutic dead-ends. A gum disease-causing species of bacteria, Porphyromonas gingivalis, is being increasingly linked with AD, given the ubiquity of gum disease amongst older populations, and studies have revealed that the bacteria causes and exacerbates AD pathology both in vitro and in vivo. P. gingivalis produce many neurotoxic molecules, including gingipain enzymes, lipopolysaccharide and phosphoglycerol dihydroceramides, and all of these have been shown to affect AD pathologies. Numerous mechanisms by which these neurotoxic species reach the brain have been proposed, and one of these is the bacteria’s use of outer membrane vesicles. This review presents the present evidence of the effects of P. gingivalis and its outer membrane vesicles, gingipains, lipopolysaccharide and phosphoglycerol dihydroceramides, on neurodegeneration in neuronal cultures, mice models and post-mortem studies, and determines how this evidence can be used to develop new treatments for AD.

Decreased O‐GlcNAcylation and mitochondrial dysfunction are involving in low glucose induced Alzheimer’s disease‐like phenotype in induced pluripotent stem cell‐derived neurons

AbstractBackgroundEvidence supporting that glucose metabolic abnormalities occur prior to Alzheimer’s disease (AD) symptoms. Reduced O‐GlcNAc (OGN) levels likely arise from impaired glucose metabolism or availability and correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model.MethodWe generated human cortical neurons from human‐induced pluripotent stem cells and treated neurons with glucose reduction media. FluoroJADE staining and cell viability assays were used to study the effects of low glucose on the degenerative status and cell viability of neurons. Abnormal protein production, phosphorylation, and accumulation were detected by western blotting and immunofluorescence staining using antibody against p‐tau and beta‐amyloid. Neurite and synaptic structure were observed by immunofluorescence staining, while neuronal network activity was detected by multi‐electrode array electrophysiological analyses. Mitochondrial abnormalities, including increased oxidative stress, reduced membrane potential, and mitochondrial dysfunction, were evaluated using CM‐H2DCFDA, JC‐1 and Seahorse, respectively.ResultWe show that lowering glucose level to 2mM leads to dramatic increases of neuron degeneration on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, long‐term low glucose treatment induces AD features in neurons, including abnormal hyperphosphorylated tau accumulation and increasing beta‐amyloid production. Besides, glucose deficiency also causes decreased neurite coverage, synapse density, and neuron network activity. Furthermore, we find that O‐GlcNAc levels are significantly reduced soon after low glucose treatment and remain low until the end of experiment. Raising O‐GlcNAc levels by thiamet‐G, inhibitor of O‐GlcNAcase, even in low glucose treated neurons, rescues low glucose‐induced AD phenotypes. Moreover, our data shows that O‐GlcNAc dysregulation causes mitochondrial abnormalities, which occur before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis.ConclusionWe established a human neuron model in which the pathological features are reproduced by glucose deficiency. This platform can serve as a tool for better understanding molecular processes involved in neurodegeneration in sAD. Our results also suggest that dysregulated O‐GlcNAc levels and mitochondrial dysfunction by glucose deficiency are involved in the onset and progression of sAD.

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau.

SummaryIn Alzheimer’s disease, soluble oligomers of the amyloid-β peptide (Aβo) trigger a cascade of events that includes abnormal hyperphosphorylation of the protein tau, which is essential for pathogenesis. However, the mechanistic link between these two key pathological proteins remains unclear. Using hippocampal slices, we show here that an Aβo-mediated increase in glutamate release probability causes enhancement of synaptically evoked N-methyl-d-aspartate subtype glutamate receptor (NMDAR)-dependent long-term depression (LTD). We also find that elevated glutamate release probability is required for Aβo-induced pathological hyperphosphorylation of tau, which is likewise NMDAR dependent. Finally, we show that chronic, repeated chemical or optogenetic induction of NMDAR-dependent LTD alone is sufficient to cause tau hyperphosphorylation without Aβo. Together, these results support a possible causal chain in which Aβo increases glutamate release probability, thus leading to enhanced LTD induction, which in turn drives hyperphosphorylation of tau. Our data identify a mechanistic pathway linking the two critical pathogenic proteins of AD.

Emerging small-molecule therapeutic approaches for Alzheimer's disease and Parkinson's disease based on targeting microRNAs.

Emerging small-molecule therapeutic approaches for Alzheimer's disease and Parkinson's disease based on targeting microRNAs.

Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice.

Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer's disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). STZ was injected into the lateral ventricle of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD.

DHCR24 Knockdown Lead to Hyperphosphorylation of Tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites by Membrane Lipid-Raft Dependent PP2A Signaling in SH-SY5Y Cells.

Accumulating data suggest that the downregulation of DHCR24 is linked to the pathological risk factors of AD, denoting a potential role of DHCR24 in AD pathogenesis. However, it remains unclear whether the downregulation of DHCR24 affects the abnormal heper-phosphorylation of tau protein, which is involved in tauopathy. In present papers, immunofluorescence and Filipin III fluorescence results showed that DHCR24 knockdown significantly lowered the level of plasma membrane cholesterol and expression level of membrane lipid-raft structural protein caveolin-1; and overexpression of DHCR24 could increase the plasma membrane cholesterol levels and facilitating caveolae structure through increase the expression of caveolin-1. PP2A is the key phosphatase involving in tau phosphorylation, which is localized in cholesterol-dependent caveola/raft lipid domains. Here, the PP2A activity was detected by western blot assay. Interestingly, the level of p-PP2Ac at Y307 (inactive) and p-GSK3β at Y216 (active) in the downstream of the PP2A signal pathway were both significantly increased in silencing DHCR24 SH-SY5Y cells, which denoted an inhibition of the PP2A and activation of GSK3β signaling. Conversely, overexpression of DHCR24 blunted the inhibition effect of PP2A and activation of GSK3β. Besides, in the SH-SY5Y cell lines we demonstrated that DHCR24 knockdown obviously induced hyperphosphorylation of tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites. In contrast, DHCR24 overexpression protects neuronal SH-SY5Y cells against the hyperphosphorylation of tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites. Furthermore, PP2A activator D-erythro-Sphingosine (DES) also obviously inhibited the hyperphosphorylation of tau induced by DHCR24 knockdown. Collectively, our findings firstly confirmed that DHCR24 knockdown obviously induced abnormal hyperphosphorylation of tau by a novel lipid raft-dependent PP2A signaling. We propose that DHCR24 downregulation led to altered cholesterol synthesis as a potential mechanism in the progression of tau hyperphosphorylation involving in AD and other tauopathies.

Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation

SummaryIt has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies.

Neurodegeneration: 2021 update.

This article reviews a collection of manuscripts in the field of neurodegenerative disease chosen from what are considered by the author to be among the 10 most important and potentially impactful topics or research trends of 2020 relevant to the field of experimental and diagnostic neuropathology. A deliberate effort was made to provide balance among disease categories covered. The result is a varied selection that includes not just individual papers but also research topics and trends. The association of COVID-19 with longer-term neurological symptoms has launched a research trend fueled by speculation that the SARS-CoV-2 might trigger neurodegenerative changes. The onslaught of transcriptomic studies has begun to give way to proteomics, with three transformative studies published examining glial contributions to Alzheimer disease, cerebral atherosclerosis in cognitive decline, and the complex sequence of post-translational modifications of the tau protein. Plasma biomarkers for Alzheimer disease have continued to make rapid advances, especially around highly sensitive assays capable of detecting different forms of abnormal hyperphosphorylated tau in peripheral blood. Two studies using cryo-electron microscopy showed the power of the approach by continuing to elucidate the diversity of filamentous tau inclusions, and a third study gave the first glimpse of α-synuclein aggregates at near atomic resolution. Another study continued to delineate how different α-synuclein conformers ("strains") target specific brain regions and lead to neurodegeneration. In Huntington's disease, we saw compelling molecular data showing how cells adapt to endoplasmic reticulum stress through the unfolded protein response. Finally, the role of astrocytes in chronic traumatic encephalopathy has emerged as a critical area of interest.

Advances in Drug Therapy for Alzheimer\u2019s Disease

SummaryAlzheimer’s disease (AD) is a chronic neurodegenerative disease that mainly causes dementia. It is a serious threat to the health of the global elderly population. Considerable money and effort has been invested in the development of drug therapy for AD worldwide. Many drug therapies are currently under development or in clinical trials, based on two known mechanisms of AD, namely, Aβ toxicity and the abnormal Tau hyperphosphorylation. Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation, neurotransmitter imbalance, oxidative damage and mitochondrial dysfunction, neuron loss and degeneration. Even so, the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited. However, multi-drug combinations may provide a new avenue for drug therapy for AD. In addition, early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.