Formation Of Neurofibrillary Tangles Research Articles

BSCI-12 BREAST TO BRAIN METASTASIS IS EXACERBATED WITH CHEMOTHERAPY THROUGH BLOOD-CEREBRAL SPINAL FLUID-BARRIER AND INDUCES ALZHEIMER’S-LIKE PATHOLOGY

Abstract Control of breast to brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have also shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through formation of neurofibrillary tangles (NFT) independently. Now, in this study we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies promote increased brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid-barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage of Tau released from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer’s-like tauopathy.

The protective effects of dietary polyphenols on Alzheimer's disease

Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disease in the hippocampus and cortex regions of the brain and is the most common cause of dementia in the elderly population among 40 million cases worldwide today, it is thought that this number will exceed up to 100 million by 2050. The disease is characterized by symptoms of memory loss, difficulty in speaking, decision making, learning, problem solving, and impaired perception of time and orientation. In its pathogenesis, the amyloid beta (Aβ) senile plaques accumulation in the extracellular synaptic spaces of the neurocortex, the formation of intracellular hyperphosphorylated tau protein deposition and neurofibrillary tangles (NFY) are important and triggered neurodegeneration mainly affects cognitive behavior and memory. Phenolic compounds are organic compounds containing a benzene ring to which one or more hydroxyl groups are attached. Studies have shown that regular consumption of polyphenols reduces the risk of developing neurodegenerative diseases. Studies have reported that polyphenols inhibit Aβ production and accumulation processes by interacting with different forms of amyloid structure. In this study, polyphenols and their therapeutic properties against AD will be discussed extensively.

Potential Roles of α-amylase in Alzheimer's Disease: Biomarker and Drug Target.

Alzheimer's disease (AD), the most common form of dementia, is pathologically characterized by the deposition of amyloid-β plaques and the formation of neurofibrillary tangles. In a neurodegenerative brain, glucose metabolism is also impaired and considered as one of the key features in AD patients. The impairment causes a reduction in glucose transporters and the uptake of glucose as well as alterations in the specific activity of glycolytic enzymes. Recently, it has been reported that α-amylase, a polysaccharide-degrading enzyme, is present in the human brain. The enzyme is known to be associated with various diseases such as type 2 diabetes mellitus and hyperamylasaemia. With this information at hand, we hypothesize that α-amylase could have a vital role in the demented brains of AD patients. This review aims to shed insight into the possible link between the expression levels of α-amylase and AD. Lastly, we also cover the diverse role of amylase inhibitors and how they could serve as a therapeutic agent to manage or stop AD progression.

Neuroprotective effect of Hypericum perforatum extract against Aluminum-maltolate induced toxicity in SH-SY5Y cells

Alzheimer's disease is multi-component neurodegenerative disorder. Oxidative stress disrupts regular functioning of metabolism in early-onset Alzheimer's disease. It causes Tau phosphorylation, formation of neurofibrillary tangle and neuron reduction. Due to intense binding of phosphorylated amino acids to aluminum, it induces self-assembly and deposition of high degree of phosphorylated cytoskeletal proteins, such as microtubule and neurofilament-associated proteins. In this study, it is aimed to consider the antioxidant potential of Hypericum perforatum extract against neurotoxicity caused by Aluminum-maltolate (Al(mal)3) and its effects on APP gene expression. Four different groups were determined to observe the impact of H. perforatum extract. After the incubation of the cells for 24 hours, only the medium was placed in the first group as control. 500 μM Al(mal)3 was added to the second group of cells. 20 μg mL-1 Hypericum perforatum extract was added to the third group. For the fourth group, 20 μg mL-1 Hypericum perforatum extract and 500 μM Al(mal)3 were added. While Al(mal)3 increased total antioxidant status levels in SH-SY5Y human neuroblastoma cells, H. perforatum extract significantly inhibited Al(mal)3 induced oxidative stress. On the other hand, H. perforatum extract significantly decreased APP gene expression levels depending on Al(mal)3 toxicity in SH-SY5Y cells. According to these results, H. perforatum extract significantly inhibited Al(mal)3 neurotoxicity against SH-SY5Y cells. To determine synergistic and antagonistic effects of H. perforatum extract content is important to examine their specific effects of together with hyperforin, which is a phytochemical produced by some of the members of the plant genus Hypericum, to discover new therapeutic agents against neurodegeneration.

Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes.

A key hallmark of Alzheimer's disease (AD) pathology is the intracellular accumulation of tau protein in the form of neurofibrillary tangles across large-scale networks of the human brain cortex. Currently, it is still unclear how tau accumulates within specific cortical systems and whether in situ genetic traits play a role in this circuit-based propagation progression. In this study, using two independent cohorts of cognitively normal older participants, we reveal the brain network foundation of tau spreading and its association with using high-resolution transcriptomic genetic data. We observed that specific connectomic and genetic gradients exist along the tau spreading network. In particular, we identified 577 genes whose expression is associated with the spatial spreading of tau. Within this set of genes, APOE and glutamatergic synaptic genes, such as SLC1A2, play a central role. Thus, our study characterizes neurogenetic topological vulnerabilities in distinctive brain circuits of tau spreading and suggests that drug development strategies targeting the gradient expression of this set of genes should be explored to help reduce or prevent pathological tau accumulation.

Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease

Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs from the human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.

Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer's disease.

The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer’s disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-β (Aβ). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro, and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aβ-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD.

Application of weighted co-expression network analysis and machine learning to identify the pathological mechanism of Alzheimer's disease

Aberrant deposits of neurofibrillary tangles (NFT), the main characteristic of Alzheimer's disease (AD), are highly related to cognitive impairment. However, the pathological mechanism of NFT formation is still unclear. This study explored differences in gene expression patterns in multiple brain regions [entorhinal, temporal, and frontal cortex (EC, TC, FC)] with distinct Braak stages (0- VI), and identified the hub genes via weighted gene co-expression network analysis (WGCNA) and machine learning. For WGCNA, consensus modules were detected and correlated with the single sample gene set enrichment analysis (ssGSEA) scores. Overlapping the differentially expressed genes (DEGs, Braak stages 0 vs. I-VI) with that in the interest module, metascape analysis, and Random Forest were conducted to explore the function of overlapping genes and obtain the most significant genes. We found that the three brain regions have high similarities in the gene expression pattern and that oxidative damage plays a vital role in NFT formation via machine learning. Through further filtering of genes from interested modules by Random Forest, we screened out key genes, such as LYN, LAPTM5, and IFI30. These key genes, including LYN, LAPTM5, and ARHGDIB, may play an important role in the development of AD through the inflammatory response pathway mediated by microglia.

Copolymer-1 as a potential therapy for mild cognitive impairment

Mild cognitive impairment (MCI) is a prodromal stage of memory impairment that may precede dementia. MCI is classified by the presence or absence of memory impairment into amnestic or non-amnestic MCI, respectively. More than 90% of patients with amnestic MCI who progress towards dementia meet criteria for Alzheimer’s disease (AD). A combination of mechanisms promotes MCI, including intracellular neurofibrillary tangle formation, extracellular amyloid deposition, oxidative stress, neuronal loss, synaptodegeneration, cholinergic dysfunction, cerebrovascular disease, and neuroinflammation. However, emerging evidence indicates that neuroinflammation plays an important role in the pathogenesis of cognitive impairment. Unfortunately, there are currently no Food and Drug Administration (FDA)-approved drugs for MCI.Copolymer-1 (Cop-1), also known as glatiramer acetate, is a synthetic polypeptide of four amino acids approved by the FDA for the treatment of relapsing-remitting multiple sclerosis. Cop-1 therapeutic effect is attributed to immunomodulation, promoting a switch from proinflammatory to anti-inflammatory phenotype. In addition to its anti-inflammatory properties, it stimulates brain-derived neurotrophic factor (BDNF) secretion, a neurotrophin involved in neurogenesis and the generation of hippocampal long-term potentials. Moreover, BDNF levels are significantly decreased in patients with cognitive impairment. Therefore, Cop-1 immunization might promote synaptic plasticity and memory consolidation by increasing BDNF production in patients with MCI.

MicroRNA-22-3p ameliorates Alzheimer’s disease by targeting SOX9 through the NF-κB signaling pathway in the hippocampus

BackgroundStudies have suggested that many down-regulated miRNAs identified in the brain tissue or serum of Alzheimer’s disease (AD) patients were involved in the formation of senile plaques and neurofibrillary tangles. Specifically, our previous study revealed that microRNA-22-3p (miR-22-3p) was significantly down-regulated in AD patients. However, the molecular mechanism underlying the down-regulation of miR-22-3p has not been comprehensively investigated.MethodsThe ameliorating effect of miR-22-3p on apoptosis of the Aβ-treated HT22 cells was detected by TUNEL staining, flow cytometry, and western blotting. The cognition of mice with stereotaxic injection of agomir or antagomir of miR-22-3p was assessed by Morris water maze test. Pathological changes in the mouse hippocampus were analyzed using hematoxylin and eosin (HE) staining, Nissl staining, and immunohistochemistry. Proteomics analysis was performed to identify the targets of miR-22-3p, which were further validated using dual-luciferase reporter analysis and western blotting analysis.ResultsThe miR-22-3p played an important role in ameliorating apoptosis in the Aβ-treated HT22 cells. Increased levels of miR-22-3p in the mouse hippocampus improved the cognition in mice. Although the miR-22-3p did not cause the decrease of neuronal loss in the hippocampus, it reduced the Aβ deposition. Proteomics analysis revealed Sox9 protein as the target of miR-22-3p, which was verified by the luciferase reporter experiments.ConclusionOur study showed that miR-22-3p could improve apoptosis and reduce Aβ deposition by acting on Sox9 through the NF-κB signaling pathway to improve the cognition in AD mice. We concluded that miR-22-3p ameliorated AD by targeting Sox9 through the NF-κB signaling pathway in the hippocampus.

A Review of CRISPR Cas9 for Alzheimer’s Disease: Treatment Strategies and Could target APOE e4, APP, and PSEN-1 Gene using CRISPR cas9 Prevent the Patient from Alzheimer’s Disease?

A Review of CRISPR Cas9 for Alzheimer’s Disease: Treatment Strategies and Could target APOE e4, APP, and PSEN-1 Gene using CRISPR cas9 Prevent the Patient from Alzheimer’s Disease? BACKGROUND: Alzheimer’s disease is a neurodegenerative disorder characterized by the formation of β-amyloid plaques and neurofibrillary tangles from hyperphosphorylated tau. Several studies suggest that targeting the deletion of the APOE e4, PSEN-1, and APP will reduce tau phosphorylation and Aβ protein accumulation, a crucial hypothesis for the causation of Alzheimer’s disease. APOE e4, PSEN-1, and APP with genome editing Clustered Regular interspersed Short Palindromic Repeats-CRISPR-related (CRISPR/Cas9) are thought to have therapeutic promise for Alzheimer’s disease.AIM: The purpose of this study was to determine whether targeting APOE e4, PSEN-1, and APP using CRISPR/Cas9 is an effective therapeutic and whether it has a long-term effect on Alzheimer’s disease.METHODS: The method used in this study summarized articles by examining the titles and abstracts of specific specified keywords. In this situation, the author picked the title and abstract that matched PubMed, Google Scholar, Science Direct, Cochrane, and the Frontiers in Neuroscience; this was followed by checking to see whether the paper was available in full-text. Eventually, the researcher will study the entire article to decide if it is valuable and relevant to the issue.RESULTS: CRISPR/Cas9 deletion of APOE e4, PSEN-1, and APP in induced pluripotent stem cells (iPSC’s) and g2576 mice as APP mutant models reduce tau phosphorylation and Aβ protein accumulation from neurofibrillary tangles and prevent cell death, vascular damage, and dementia. Furthermore, CRISPR/Cas9 deletion in APOE e4, PSEN-1, and APP improved neuronal cell resilience to oxidative stress and inflammation.CONCLUSION: APOE e4, PSEN-1, and APP deletion by genome editing CRISPR/Cas9 is effective to reduce tau phosphorylation and Aβ protein accumulation from neurofibrillary tangles, cell death, vascular damage, and dementia. However, further research is needed to determine the side effects and safety of its use.

Prominent Effects of Berbamine Hydrochloride on Alzheimer's Disease Model Mice.

Very few anti-Alzheimer’s disease (AD) drugs are clinically available at present due to the complex mechanism of Alzheimer’s disease. For the purpose of discovering potential anti-AD drugs in bisbenzylisoquinoline alkaloids, the anti-AD function and the mechanism of the function of berbamine hydrochloride (BBMH) were studied. Three kinds of AD model mice, double transgenic APP/PS1 AD mice, Gal-Alu AD mice induced by the intraperitoneal injection of d-galactose combined with the intragastric administration of aluminum trichloride, and Alu AD-like mice induced by stereotactic brain injection of aluminum trichloride, were administered with BBMH for 40 days at a dosage of 280 mg/kg/d. The effects of BBMH on the learning and memory behavior of the AD mice were studied through the Morris water maze experiment, and the influences of BBMH on the pathological features of AD, including the deposition of Aβ, the lesions of pyramidal cells (neurons), and the formation of neurofibrillary tangles, were studied by the immunohistochemical staining, hematoxylin-eosin staining, and silver staining of the brain tissues of the mice. The water maze experiment showed that BBMH could significantly improve the learning and memory abilities of three kinds of treated mice. Immunohistochemical staining showed that BBMH could significantly reduce the deposition of Aβ in the brain tissues of treated mice. Hematoxylin-eosin staining showed that BBMH could significantly alleviate the lesions of pyramidal cells in the hippocampal tissue of the mice. Silver staining showed that BBMH could significantly reduce the formation of neurofibrillary tangles in the hippocampal tissue of the mice. These results indicated that BBMH has significant anti-AD effects and the potential as an anti-AD drug. Western blot analysis of the brain tissue of the mice showed that the expression level of calpain, a Ca2+-dependent proteolytic enzyme, was significantly inhibited and the expression level of SelK, a selenoprotein mainly expressed in immune cells, was significantly increased. It is speculated that the anti-AD effect of BBMH is related to the improvement of the phagocytosis of microglial cells in brain tissues and macrophages migrated into the brain as well as the regulation of calcium homeostasis and calcium-dependent proteases in the brain tissues of the mice.

Reassessment of Neuronal Tau Distribution in Adult Human Brain and Implications for Tau Pathobiology

Tau is a predominantly neuronal, soluble and natively unfolded protein that can bind and stabilize microtubules in the central nervous system. Tau has been extensively studied over several decades, especially in the context of neurodegenerative diseases where it can aberrantly aggregate to form a spectrum of pathological inclusions. The presence of tau inclusions in the form of neurofibrillary tangles, neuropil threads and dystrophic neurites within senile plaques are essential and defining features of Alzheimer’s disease. The current dogma favors the notion that tau is predominantly an axonal protein, and that in Alzheimer’s disease there is a redistribution of tau towards the neuronal soma that is associated with the formation of pathological inclusions such as neurofibrillary tangles and neuropil threads. Using novel as well as previously established highly specific tau antibodies, we demonstrate that contrary to this overwhelmingly accepted fact, as asserted in numerous articles and reviews, in adult human brain, tau is more abundant in cortical gray matter that is enriched in neuronal soma and dendrites compared to white matter that is predominantly rich in neuronal axons. Additionally, in Alzheimer’s disease tau pathology is significantly more abundant in the brain cortical gray matter of affected brain regions compared to the adjacent white matter regions. These findings have important implications for the biological function of tau as well as the mechanisms involved in the progressive spread of tau associated with the insidious nature of Alzheimer’s disease.

A Histochemical Analysis of Neurofibrillary Tangles in Olfactory Epithelium, a Study Based on an Autopsy Case of Juvenile Alzheimer’s Disease

The pathological changes of Alzheimer’s disease (AD) begin 10–20 years before clinical onset, and it is therefore desirable to identify effective methods for early diagnosis. The nasal mucosa is a target tissue for measuring AD-related biomarkers because the olfactory nerve is the only cranial nerve that is exposed to the external environment. We describe an autopsy case of rapidly advanced juvenile AD (JAD), focusing on the olfactory system. The formation of senile plaques, neurofibrillary tangles (NFTs), and neuropil threads was examined in the temporal cortex, hippocampus, olfactory bulb, and olfactory and respiratory epithelia in the bilateral olfactory clefts. Neurodegenerative changes in the olfactory and respiratory epithelia and the pathological deposition of amyloid β42 (Aβ42) and phosphorylated tau were also examined. As a result, senile plaques, NFTs, and neuropil threads were found in the temporal cortex, hippocampus, and olfactory bulb. NFTs were also found in the olfactory epithelium. Degenerated olfactory cells and their axons stained positive for phosphorylated tau. Supporting cells in the degenerated olfactory epithelium stained positive for Aβ42. In conclusion, pathological biomarkers of AD were expressed in the degenerated olfactory epithelium of this JAD patient. This observation suggests that nasal samples may be useful for the diagnosis of AD.

Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer’s disease

Concerned by the urgent need to explore new approaches for the treatment of Alzheimer’s disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain.Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine.The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC50 = 0.46 µM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC50 = 2.2 µM). This compound exhibited a roughly 12-fold increase in activity compared to galantamine, one of the currently marketed drugs against AD, and a selective AChE inhibitor, and virtually the same activity as rivastigmine, a selective BuChE inhibitor. Furthermore, it was also endowed with a strong inhibitory activity against human OGA, within the nanomolar range (IC50 = 0.053 µM for hOGA, >100 µM for hHexB), and, thus, with an outstanding selectivity (IC50(hHexB)/IC50(hOGA) > 1887). The title compounds also exhibited an excellent selectivity against a panel of glycosidases and a negligible cytotoxicity against tumor and non-tumor cell lines.Docking simulations performed on the three target enzymes (AChE, BuChE, and OGA) revealed the key interactions to rationalize the biological data.

Atypical Parkinson's syndrome in old age

Atypical Parkinson syndromes represent aneuropathologically heterogeneous group and include the clinical entities dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The DLB and MSA are characterized by deposition of the protein alpha-synuclein (synucleinopathy), PSP and CBD are characterized by deposition of tau protein, often in the form of neurofibrillary tangles in nerve and glial cells (tauopathy). Misfolding and aggregation of the aforementioned proteins causes degeneration of the affected cell populations but the disease also spreads to anatomically neighboring brain regions, thus contributing to disease progression. The clinical characteristics (poor response to dopaminergic treatment, ataxia, apraxia, vertical gaze palsy and rapid progression) enable a differentiation from idiopathic Parkinson's disease.

Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model.

Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer’s disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and β-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal–membrane-signaling axis.

Retinal examination with curcumin in Alzheimer's disease

Background: Currently there is no definite cure for Alzheimer's therefore early detection is critical. Undetected Alzheimer's Disease (AD) can lead to severe accidents, neglecting to take essential medications, injury to oneself or others, and/or financial problems. Currently, biomarkers are the most promising way to detect Alzheimer's early on. Biomarkers such as beta-amyloid and tau levels taken through invasive mehods or brain scans that involve radiation are among them [20]. Objectives: Alzheimer's Disease (AD) presents itself in the body with an increase in ß-amyloid (Aß) plaque deposition, neurofibrillary tangle formation (NFT), and inflammation. As the retina is an extension of the brain and the brain structure it is possible to detect misfolded proteins via retinal examination non-invasively. One of the main objectives of this study is to determine the effectiveness of curcumin which is a phytochemical which can bind to amyloid-beta and Tau and can be used both for the diagnosis and early treatment of AD. The aim of this study was to discover the binding property of curcumin to both Tau and AB in the retina as a potential biomarker for AD.Methods: In this study, 20 patients were invited with mild AD who had undergone retinal examination within the past 2 years. All the patients had retinal imaging with curcumin which revealed misfolded proteins during the examination and then they were advised to take daily curcumin. The mean age of the patients was 71, and the patients were instructed to take Curcumin Meriva in 500 mg supplements once daily after their prior examinations. All patients had tests repeated with FAF and Heidelberg Spectralis OCT device. The regions with abnormal lesions on FAF were detected and the layer of the defect was scanned by OCT plus compared with the previous imaging of the patients. The images were examined in a masked fashion by 2 specialists.Results: The images disclosed hyperfluorescent lesions on FAF and OCT revealed accumulations in the inner layers of the retina. Some accumulations had dot shapes and others had fibril-tangle shapes. Some lesions were present in prior exams, but they were more pronounced and shinier after curcumin use. Their size and shape were in concordance with misfolded proteins in the brain [Fig.2,3,4,5,6].Conclusion: Retinal examination with curcumin revealed AB plaques in the retina in prior studies. Our study is the first that may demonstrate an easy way to detect the culprit plaque Tau inside the retina of live patients. Keywords: Alzheimer's Disease, curcumin, neurofibrillary tangle formation (NFT), inflammation, retina, ß-amyloid (Aß) plaque deposition, Misfolded proteins, Fundus Autofluorescence (FAF), Tau, amyloid-beta, treatment

Does Dementia Have a Microbial Cause?

The potential contribution of pathogenic microbes to dementia-inducing disease is a subject of considerable importance. Alzheimer's disease (AD) is a neurocognitive disease that slowly destroys brain function, leading to cognitive decline and behavioral and psychiatric disorders. The histopathology of AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide in the form of parenchymal plaques and abnormal aggregated tau protein in the form of neurofibrillary tangles. Observational, epidemiological, experimental, and pathological studies have generated evidence for the complexity and possible polymicrobial causality in dementia-inducing diseases. The AD pathogen hypothesis states that pathogens and microbes act as triggers, interacting with genetic factors to initiate the accumulation of Aβ, hyperphosphorylated tau protein (p-tau), and inflammation in the brain. Evidence indicates that Borrelia sp., HSV-1, VZV (HHV-2), HHV-6/7, oral pathogens, Chlamydophila pneumoniae, and Candida albicans can infect the central nervous system (CNS), evade the immune system, and consequently prevail in the AD brain. Researchers have made significant progress in understanding the multifactorial and overlapping factors that are thought to take part in the etiopathogenesis of dementia; however, the cause of AD remains unclear.

Changes in glial cell phenotypes precede overt neurofibrillary tangle formation, correlate with markers of cortical cell damage, and predict cognitive status of individuals at Braak III-IV stages

Clinico-pathological correlation studies show that some otherwise healthy elderly individuals who never developed cognitive impairment harbor a burden of Alzheimer’s disease lesions (plaques and tangles) that would be expected to result in dementia. In the absence of comorbidities explaining such discrepancies, there is a need to identify other brain changes that meaningfully contribute to the cognitive status of an individual in the face of such burdens of plaques and tangles. Glial inflammatory responses, a universal phenomenon in symptomatic AD, show robust association with degree of cognitive impairment, but their significance in early tau pathology stages and contribution to the trajectory of cognitive decline at an individual level remain widely unexplored. We studied 55 brains from individuals at intermediate stages of tau tangle pathology (Braak III-IV) with diverging antemortem cognition (demented vs. non-demented, here termed `resilient’), and age-matched cognitively normal controls (Braak 0-II). We conducted quantitative assessments of amyloid and tau lesions, cellular vulnerability markers, and glial phenotypes in temporal pole (Braak III-IV region) and visual cortex (Braak V-VI region) using artificial-intelligence based semiautomated quantifications. We found distinct glial responses with increased proinflammatory and decreased homeostatic markers, both in regions with tau tangles (temporal pole) and without overt tau deposits (visual cortex) in demented but not in resilient. These changes were significantly associated with markers of cortical cell damage. Similar phenotypic glial changes were detected in the white matter of demented but not resilient and were associated with higher burden of overlying cortical cellular damage in regions with and without tangles. Our data suggest that changes in glial phenotypes in cortical and subcortical regions represent an early phenomenon that precedes overt tau deposition and likely contributes to cell damage and loss of brain function predicting the cognitive status of individuals at intermediate stages of tau aggregate burden (Braak III-IV).