• BMB Reports
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• v.51 no.6
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• pp.265-273
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• 2018

Tau protein is encoded in the microtubule-associated protein tau (MAPT) gene and contributes to the stability of microtubules in axons. Despite of its basic isoelectric point and high solubility, tau is often found in intraneuronal filamentous inclusions such as paired helical filaments (PHFs), which are the primary constituent of neurofibrillary tangles (NFTs). This pathological feature is the nosological entity termed "tauopathies" which notably include Alzheimer's disease (AD). A proteinaceous signature of all tauopathies is hyperphosphorylation of the accumulated tau, which has been extensively studied as a major pharmacological target for AD therapy. However, in addition to phosphorylation events, tau undergoes a number of diverse posttranslational modifications (PTMs) which appear to be controlled by complex crosstalk. It remains to be elucidated which of the PTMs or their combinations have pro-aggregation or anti-aggregation properties. In this review, we outline the consequences of and communications between several key PTMs of tau, such as acetylation, phosphorylation, and ubiquitination, focusing on their roles in aggregation and degradation. We place emphasis on the structure of tau protofilaments from the human AD brain, which may be good targets to modulate etiological PTMs which cause tau aggregation.

• BMB Reports
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• v.49 no.8
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• pp.405-413
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• 2016

Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders.

• Biomolecules & Therapeutics
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• v.22 no.3
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• pp.176-183
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• 2014

Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer's disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta ($A{\beta}$) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Ab-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in $A{\beta}$-induced neurotoxicity. In mice with $A{\beta}$-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Ab-induced neurotoxicity. Moreover, HCW, which had an $IC_{50}$ value of $79.7{\mu}g/ml$ for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD.

• Korean Journal of Biological Psychiatry
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• v.10 no.2
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• pp.97-106
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• 2003

Criticisms about amyloid cascade hypothesis of Alzheimer's disease(AD) are based on the findings, first, that the degree of dementia does not correlate with the number of plaques, and second, that the neurofibrillary tangle formation seems to predate plaque formation. In addition, neurofibrillary tangle counts correlate well with the degree of cognitive impairment. These findings suggest the independent importance of tau abnormality in AD research which is involved in the neurofibrillary tangle formation. Recently, tau pathology without amyloid deposits and mutations in tau protein gene were reported to be the major pathogenic mechanism in Pick's disease, progressive supranuclear palsy, corticobasal degeneration and FTDP-17(frontotemporal dementia and parkinsonism linked with chromosome 17). These data suggest that understanding the causes and consequences of tau dysfunction might give new clinical and therapeutic solutions to many known tauopathies.

• BMB Reports
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• v.48 no.5
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• pp.243-248
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• 2015

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). As such, functions and dysfunctions of LRRK2 in PD have been the subject of extensive investigation. In addition to PD, increasing evidence is suggesting that LRRK2 is associated with a wide range of diseases. Genome-wide association studies have implicated LRRK2 in Crohn's disease (CD) and leprosy, and the carriers with pathogenic mutations of LRRK2 show increased risk to develop particular types of cancer. LRRK2 mutations are rarely found in Alzheimer's disease (AD), but LRRK2 might play a part in tauopathies. The association of LRRK2 with the pathogenesis of apparently unrelated diseases remains enigmatic, but it might be related to the yet unknown diverse functions of LRRK2. Here, we reviewed current knowledge on the link between LRRK2 and several diseases, including PD, AD, CD, leprosy, and cancer, and discussed the possibility of targeting LRRK2 in such diseases. [BMB Reports 2015; 48(5): 243-248]

• Journal of the Korean Society of Radiology
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• v.83 no.3
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• pp.453-472
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• 2022

Over the past decades, the immense clinical need for early detection methods and treatments for dementia has become a priority worldwide. The advances in PET biomarkers play increasingly important roles in understanding disease mechanisms by demonstrating the protein pathology underlying dementia in the brain. Amyloid-β and tau deposition in PET images are now key diagnostic biomarkers for the Alzheimer's disease continuum. The inclusion of biomarkers in the diagnostic criteria has achieved a paradigm shift in facilitating early differential diagnosis, predicting disease prognosis, and influencing clinical management. Furthermore, in vivo images showing pathology could become prognostic as well as surrogate biomarkers in therapeutic trials. In this review, we focus on recent developments in radiotracers for amyloid-β and tau PET imaging in Alzheimer's disease and other neurodegenerative diseases. Further, we introduce their potential application as future perspectives.

• Dementia and Neurocognitive Disorders
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• v.17 no.4
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• pp.163-173
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• 2018

Background and Purpose: Behavioral variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia, which has clinical symptoms of progressive personality and behavioral changes with deterioration of social cognition and executive functions. The pathology of bvFTD is known to be tauopathy or TDP-43 equally. We analyzed the $^{18}F-THK5351$ positron emission tomography (PET) scans, which were recently developed tau PET, in patients with clinically-diagnosed bvFTD. Methods: Forty-eight participants, including participants with behavioral variant frontotemporal dementia (bvFTD, n=3), Alzheimer's disease (AD, n=21) and normal cognition (NC, n=24) who completed 3T magnetic resonance images, $^{18}F-THK5351$ PET scans, and detailed neuropsychological tests were included in the study. Voxel-wise statistical analysis and region of interest (ROI)-based analyses were performed to evaluate the retention of THK in bvFTD patients. Results: In the voxel-based and ROI-based analyses, patients with bvFTD showed greater THK retention in the prefrontal, medial frontal, orbitofrontal, anterior cingulate, insula, anterior inferior temporal and striatum regions compared to NC participants. Left-right asymmetry was noted in the bvFTD patients. A patient with extrapyramidal symptoms showed much greater THK retention in the brainstem. Conclusions: The distribution of THK retention in the bvFTD patients was mainly in the frontal, insula, anterior temporal, and striatum regions which are known to be the brain regions corresponding to the clinical symptoms of bvFTD. Our study suggests that $^{18}F-THK5351$ PET imaging could be a supportive tool for diagnosis of bvFTD.