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Abstract Background Alzheimer's disease is accompanied by an abnormal high accumulation of cis-P tau. However, the long-term changes in behavior following tau accumulation remains under debate. The present study investigated the long-term effects of tauopathy on learning and memory, synaptic plasticity, and hippocampal cell numbers. Results Cis-P tau was microinjected into the dorsal hippocampus to generate Alzheimer’s like-disease model in C57BL/6 mice. Cis-P tau injected animals showed a significant impairment in learning and memory in Y-maze and Barnes maze tests. In another group of animals, the generation of long-term potentiation (LTP) was evaluated in hippocampal slices 7 months after cis-P tau injection. LTP induction was disrupted only in the dorsal but not ventral hippocampal slices. The basal synaptic transmission was also reduced in dorsal hippocampal slices. In addition, hippocampal sampling was done, and the number of cells was assessed by Nissl staining. Obtained results indicated that the number of survived cells was significantly reduced in the dorsal and ventral hippocampus of cis P-tau injected animals compared to the animals in control group. However, the decrement of cell number was higher in the dorsal compared to the ventral hippocampus. Conclusions In conclusion, intra-hippocampal cis-P tau injection produced learning and memory impairment at 7 months after its injection. This impairment might result from LTP disruption and a significant decrease in the number of neurons in the dorsal hippocampus. Graphical Abstract

Background: Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2∼3% in the population over 65. Recent studies have reported enhancing confirmation of tau pathology in PD, however, α‐synuclein accumulation is the significant pathological hallmark of PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further clarification the development of α‐synuclein and tau pathologies. Method: We employed several PD models, containing cultured neurons treated with either 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) or with recombinant α‐synuclein. Furthermore, we examined dopaminergic neurons of cytokine Interferon‐β knock‐out. Moreover, we tested rats administrated with 6‐hydroxydopamine, Rhesus monkeys injected with MPTP neurotoxin, and then human post‐mortem brains. Result: We observed the α‐synuclein phosphorylation triggers tau pathogenicity. Moreover, we found more widespread phosphorylated tau than α‐synuclein with prion‐like nature in various brain areas. We optionally omitted P‐tau or P‐α‐synuclein from cytokine interferon‐β knock out with respective monoclonal antibodies. We observed that tau immunotherapy prevented neurodegeneration more than α‐synuclein exclusion. Conclusion: Our observations show that the pathogenic tau could be one of the prominent causes of extensive neurodegeneration triggered by PD. Consequently, we could recommend an impressive therapeutic aims to fight the devastating disorder. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury., Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults (1), and in the USA approximately 2.5 million people suffer TBI each year [...]

Early detection of cis phosphorylated tau (cis P-tau) may help as an effective treatment to control the progression of Alzheimer's disease (AD). Recently, we introduced for the first time a monoclonal antibody (mAb) with high affinity against cis P-tau. In this study, the cis P-tau mAb was utilized to develop a label-free immunosensor. The antibody was immobilized onto a gold electrode and the electrochemical responses to the analyte were acquired by electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and differential pulse voltammetry (DPV). The immunosensor was capable of selective detection of cis P-tau among non-specific targets like trans P-tau and major plasma proteins. A wide concentration range (10 × 10−14 M–3.0 × 10−9 M) of cis P-tau was measured in PBS and human serum matrices with a limit of detection of 0.02 and 0.05 pM, respectively. Clinical applicability of the immunosensor was suggested by its long-term storage stability and successful detection of cis P-tau in real samples of cerebrospinal fluid (CSF) and blood serum collected from human patients at different stages of AD. These results suggest that this simple immunosensor may find great application in clinical settings for early detection of AD which is an unmet urgent need in today's healthcare services. [ABSTRACT FROM AUTHOR]

Background: Recent research has investigated the connection between Diabetes Mellitus (DM) and Alzheimer’s Disease (AD). Insulin resistance plays a crucial role in this interaction. Studies have focused on dysregulated proteins to disrupt this connection. Non-coding RNAs (ncRNAs), on the other hand, play an important role in the development of many diseases. They encode the majority of the human genome and regulate gene expression through a variety of mechanisms. Consequently, identifying significant ncRNAs and utilizing them as biomarkers could facilitate the early detection of this cross-talk. On the other hand, computational-based methods may help to understand the possible relationships between different molecules and conduct future wet laboratory experiments. Materials and methods: In this study, we retrieved Genome-Wide Association Study (GWAS, 2008) results from the United Kingdom Biobank database using the keywords “Alzheimer’s” and “Diabetes Mellitus.” After excluding low confidence variants, statistical analysis was performed, and adjusted p-values were determined. Using the Linkage Disequilibrium method, 127 significant shared Single Nucleotide Polymorphism (SNP) were chosen and the SNP-SNP interaction network was built. From this network, dense subgraphs were extracted as signatures. By mapping each signature to the reference genome, genes associated with the selected SNPs were retrieved. Then, protein-microRNA (miRNA) and miRNA-long non-coding RNA (lncRNA) bipartite networks were built and significant ncRNAs were extracted. After the validation process, by applying the scoring function, the final proteinmiRNA-lncRNA tripartite network was constructed, and significant miRNAs and lncRNAs were identified. Results: Hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-423-5p, and hsamiR-3184-5p, the four most significant miRNAs, as well as NEAT1, XIST, and KCNQ1OT1, the three most important lncRNAs, and their interacting proteins in the final tripartite network, have been proposed as new candidate biomarkers in the cross-talk between DM and AD. The literature review also validates the obtained ncRNAs. In addition, miRNA/lncRNA pairs; hsa-miR124-3p/KCNQ1OT1, hsa-miR-124-3p/NEAT1, and hsa-miR-124-3p/XIST, all expressed in the brain, and their interacting proteins in our final network are suggested for future research investigation. Conclusion: This study identified 127 shared SNPs, 7 proteins, 15 miRNAs, and 11 lncRNAs involved in the cross-talk between DM and AD. Different network analysis and scoring function suggested the most significant miRNAs and lncRNAs as potential candidate biomarkers for wet laboratory experiments. Considering these candidate biomarkers may help in the early detection of DM and AD co-occurrence. [ABSTRACT FROM AUTHOR]

Diabetes mellitus may cause tau protein hyperphosphorylation and neurodegeneration, but the exact mechanism by which diabetic conditions induce tau pathology remains unclear. Tau protein hyperphosphorylation is considered a major pathological hallmark of neurodegeneration and can be triggered by diabetes. Various tau‐directed kinases, including P38, can be activated upon diabetic stress and induce tau hyperphosphorylation. Despite extensive research efforts, the exact tau specie(s) and kinases driving neurodegeneration in diabetes mellitus have not been clearly elucidated. We herein employed different techniques to determine the exact molecular mechanism of tau pathology triggered by diabetes in in vivo and in vitro models. We showed that diabetes‐related stresses and glucose metabolism deficiency could induce cis P‐tau (an early driver of the tau pathology) accumulation in the midbrain and corpus callosum of the diabetic mice models and cells treated with 2‐deoxy‐D‐glucose, respectively. We found that the active phosphorylated level of P38 was increased in the treated cells and diabetic mice models. We observed that oxidative stress activated P38, which directly and indirectly drove tau pathology in the GABAergic and glutamatergic neurons of the midbrain of the diabetic mice after 96 h, which accumulated in the other neighboring brain areas after 2 months. Notably, P38 inhibition suppressed tau pathogenicity and risk‐taking behaviors in the animal models after 96 h. The data establish P38 as a central mediator of diabetes mellitus‐induced tau pathology. Our findings provide mechanistic insight into the consequences of this metabolic disorder on the nervous system. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is the main cause of death and disability among young people. Following TBI, immune system activation and cytokine release induce kinase activity and hyperphosphorylation of tau protein, a structural molecule in axonal microtubules. The cis configuration of phosphorylated tau at Th231 is extremely neurotoxic and is having a prion nature, spreads to brain areas as well as CSF. We examined the cerebrospinal fluid (CSF) cis p-tau levels in 32 TBI patients and 5 non-TBI controls to find out the correlation with TBI severity. CSF samples were drained 5–7 days after TBI and subjected for ELISA analysis with anti cis p-tau and β-amyloid antibodies. We had no patients with mild TBI, two patients with moderate (6.2%), 23 patients with severe (71.9%), and 7 patients with critical TBI (21.9%). While mean CSF β-amyloid in TBI and control groups did not show a statistically significant difference, the mean CSF cis p-tau level was significantly higher in the TBI group than the control samples. Also, intergroup analysis demonstrated that CSF cis p-tau levels were statistically different according to the head injury severity. Although CSF cis p-tau increased in the TBI patients, β-amyloid did not show a significant difference between patients and controls. Also, we observed an obvious negative correlation between CSF cis p-tau levels and GCS scores. Therefore, future researches on suppression of cis P-tau production or removing previously produced cis P-tau could be a suitable approach in treating TBI in order to prevent tauopathies and future neurodegeneration. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly increased the pressure on healthcare systems worldwide. The pathogenesis of AD is being extensively investigated, yet several unknown key components remain. Therefore, we aimed to extract new knowledge from existing data. Ten gene expression datasets from different brain regions including the hippocampus, cerebellum, entorhinal, frontal and temporal cortices of 820 AD cases and 626 healthy controls were analyzed using the robust rank aggregation (RRA) method. Our results returned 1713 robust differentially expressed genes (DEGs) between five brain regions of AD cases and healthy controls. Subsequent analysis revealed pathways that were altered in each brain region, of which the GABAergic synapse pathway and the retrograde endocannabinoid signaling pathway were shared between all AD affected brain regions except the cerebellum, which is relatively less sensitive to the effects of AD. Furthermore, we obtained common robust DEGs between these two pathways and predicted three miRNAs as potential candidates targeting these genes; hsa-mir-17-5p, hsa-mir-106a-5p and hsa-mir-373-3p. Three transcription factors (TFs) were also identified as the potential upstream regulators of the robust DEGs; ELK-1, GATA1 and GATA2. Our results provide the foundation for further research investigating the role of these pathways in AD pathogenesis, and potential application of these miRNAs and TFs as therapeutic and diagnostic targets. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder, in which amyloid precursor protein (APP) misprocessing and tau protein hyperphosphorylation are well-established pathogenic cascades. Despite extensive considerations, the central mediator of neuronal cell death upon AD remains under debate. Therefore, we examined the direct interplay between tauopathy and amyloidopathy processes. We employed primary culture neurons and examined pathogenic P-tau and Aβ oligomers upon hypoxia treatment by immunofluorescence and immunoblotting. We observed both tauopathy and amyloidopathy processes upon the hypoxia condition. We also applied Aβ1–42 or P-tau onto primary cultured neurons. We overexpressed P-tau in SH-SY5Y cells and found Aβ accumulation. Furthermore, adult male rats received Aβ1–42 or pathogenic P-tau in the dorsal hippocampus and were examined for 8 weeks. Learning and memory performance, as well as anxiety behaviors, were assessed by Morris water maze and elevated plus-maze tests. Both Aβ1–42 and pathogenic P-tau significantly induced learning and memory deficits and enhanced anxiety behavior after treatment 2 weeks. Aβ administration induced robust tauopathy distribution in the cortex, striatum, and corpus callosum as well as CA1. On the other hand, P-tau treatment developed Aβ oligomers in the cortex and CA1 only. Our findings indicate that Aβ1–42 and pathogenic P-tau may induce each other and cause almost identical neurotoxicity in a time-dependent manner, while tauopathy seems to be more distributable than amyloidopathy. [ABSTRACT FROM AUTHOR]

Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2~3% in the population over 65. α‐Synuclein aggregation is the major pathological hallmark of PD. However, recent studies have demonstrated enhancing evidence of tau pathology in PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further investigate the development of α‐synuclein and tau pathology. We employed various PD models, including cultured neurons treated with either 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) or with recombinant α‐synuclein. Also, we studied dopaminergic neurons of cytokine Interferon‐β knock‐out. Moreover, we examined rats treated with 6‐hydroxydopamine, Rhesus monkeys administrated with MPTP neurotoxin, and finally, human post‐mortem brains. We found the α‐synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α‐synuclein with prion‐like nature in various brain areas. We optionally removed P‐tau or P‐α‐synuclein from cytokine interferon‐β knock out with respective monoclonal antibodies. We found that tau immunotherapy suppressed neurodegeneration more than α‐synuclein elimination. Our findings indicate that the pathogenic tau could be one of the leading causes of comprehensive neurodegeneration triggered by PD. Thus, we can propose an efficient therapeutic target to fight the devastating disorder. [ABSTRACT FROM AUTHOR]

The Wnt pathway is the most important cascade in the nervous system; evidence has indicated that deregulation of the Wnt pathway induced pathogenic hallmarks of neurodegenerative diseases. Glycogen synthase kinase‐3β (GSK‐3β) as the main member of the Wnt pathway increases tau inclusions, the main marker in the neurodegenerative diseases. Phosphorylated tau is observed in the pre‐tangle of the neurons in the early stage of neurodegenerative diseases. The researchers always try to improve pharmacological approaches of new therapeutic strategies to the treatment of neurodegenerative diseases that are required to represent a significant entry point by understanding the theoretical interactions of the molecular pathways. In this review, we have discussed the recent knowledge about the canonical and non‐canonical Wnt signalling pathway, GSK‐3β, Wnt/β‐catenin antagonists, tau phosphorylation, and their important roles in the neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex etiology. Among the neurotransmitter abnormalities that have been investigated in AD, the dopaminergic system has been intensively studied as a key neurotransmitter system involved with emotion and cognition. The dopaminergic system undergoes several changes during the neuropathological aging process. In general, some studies suggested that dopamine plays a major role in synaptic plasticity mechanisms. Interestingly, in AD, the dysfunction of dopaminergic transmission has been hypothesized as a new player in the pathophysiology of AD. On the other hand, stimulation of dopaminergic input to the hippocampus, ventral tegmental area, improved working and spatial memory in mice model of Alzheimer's disease. In this study we assessed the effect of dopamine receptors on learning and memory and synaptic plasticity in Alzheimer's like disease mice model. Method: One month after bilaterally intra hippocampal injection of cis‐ P tau, adult male mice received D1 and D2 receptor antagonist, after 5 minute, induced high‐frequency ventral tegmental area stimulation for 30 min/ 5 day, and animals were assessed for changes in learning and memory. Short term and long term memory was assessed respectively by Y maze and Barnes maze and also synaptic plasticity was studied by in vitro evoked‐ field potential recording. Result: Hippocampal cis‐ P tau injection as a new mice model of Alzheimer's disease produced spatial and working memory impairment and also disrupted long term potentiation in striatum radiatum of hippocampus. Applying VTA‐DBS ameliorated memory impairment, with no effects in the control group. Further, in vitro evoked field potential recording showed a restoration of long term potentiation (LTP). Using D2 receptor antagonist, has no effect on learning and memory improvement after stimulation of ventral tegmental area but using D1 receptor antagonist impaired learning and memory. Applying dopamine on hippocampal slice restored LTP and D1 receptor antagonist had no effect on LTP disruption, but D2 receptor antagonist restore LTP. Conclusion: These results indicate that ventral tegmental area stimulation might mitigate memory dysfunction and synaptic plasticity in cis‐P tau accumulation by D1 receptor and phasic release of dopamine. [ABSTRACT FROM AUTHOR]

Tau is a microtubule-associated protein, which is highly expressed in the central nervous system as well as ocular neurons and stabilizes microtubule structure. It is a phospho-protein being moderately phosphorylated under physiological conditions but its abnormal hyperphosphorylation or some post-phosphorylation modifications would result in a pathogenic condition, microtubule dissociation, and aggregation. The aggregates can induce neuroinflammation and trigger some pathogenic cascades, leading to neurodegeneration. Taking these together, targeting pathogenic tau employing tau immunotherapy may be a promising therapeutic strategy in fighting with cerebral and ocular neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic, predominantly immune-mediated degenerative disease of the central nervous system. Due to prolonged use of immunomodulatory and immunosuppressive medications, vaccine hesitancy could be common among MS patients. Our main aim in the current study was to evaluate the willingness and acceptability of COVID-19 vaccination in patients with MS. In our multicenter cross-sectional questionnaire-based clinical study, 892 patients completed the questionnaire between May to June 2021. The questionnaire consisted of demographic data, MS disease-related factors, history of COVID-19 infection/vaccination, and any existing comorbidities. Statistical analysis was performed using SPSS software version 19. Overall, 68% of the participants expressed willingness to be vaccinated. Major causes of vaccine refusal in our patients were the fear of reducing the efficacy of disease modifying drugs (DMDs) upon vaccination as well as distrusting the vaccines and overestimation bias in the power of their innate immunity and potential COVID-19 resistance. Some demographic factors affected vaccination enthusiasm in our study. Our findings did not show significant correlation between the age and comorbidity and vaccine willingness. Only one-third of our patients received their vaccine information from healthcare providers. The majority of them received these data from official broadcasting channels and social media. However, despite several concerns, the willingness of COVD-19 vaccination in the Iranian MS patients is remarkable. [ABSTRACT FROM AUTHOR]

Purpose: Age-related macular degeneration (AMD) as the leading cause of central visual loss in the developed countries has extensive pathologic similarities with Alzheimer's disease (AD). Saitohin rs62063857 Q7 R polymorphism is associated with increased risk of AD though we decided to evaluate the possible association of this polymorphism with advanced AMD. Materials and Methods: 152 advanced AMD patients (134 wet AMD and 18 geographic atrophy) and 75 healthy controls included in this study. Cases and controls went through a standard ophthalmologic examination by a retinal specialist. Saitohin gene rs62063857 polymorphism determined by using PCR technique and restriction enzyme HinFI. To evaluate the differences between groups we used t-test, Chi-Squared and one-tailed Fisher exact test. Results: Distribution of genotypes was not significantly different between total AMD or wet AMD patients compared to that of controls (total AMD RR+QR: OR = 1.51, CI = 0.82–2.79, P =.12; wet AMD RR+QR: OR = 1.39, CI = 0.74–2.59, P =.19). The RR+QR genotypes were significantly higher in dry AMD group compared to that of controls (RR+QR: OR = 2.75, CI = 0.96–7.9, P =.05). Conclusion: Our results showed that although STH Q7 R polymorphism was not associated with wet AMD susceptibility it was significantly associated with geographic atrophy. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.