Symposia
The Pathogenesis of Neurodegenerative diseases on the Oligomer Hypothesis／オリゴマー仮説に基づいて神経変性疾患の病態を考える |
|---|
| 2S8-1
The consideration of Alzheimer's disease from the view of Aβ oligomer
Kenjiro Ono
Dept of Neurol. Sch of Med, Showa Univ
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the aged people. Currently, no disease-modifying therapeutic agents are available for AD patients. Alzheimer’s disease (AD) is characterized by the accumulation of amyloid plaques formed by the amyloid β-protein (Aβ), a 40-42 amino acid peptide and neurofibrillary tangles, composed of paired helical filaments, the principal component of which is tau. Amyloid β-protein (Aβ) is the primary component of amyloid plaques, and has been suggested to be responsible for the pathogenesis of AD (amyloid hypothesis). Aβ molecules tend to aggregates to form oligomers, protofibrils (PF), and Aβ fibrils. Although these Aβ aggregates may cause neuronal injury, recent evidence supports the hypothesis that intermediate aggregates of Aβ, such as PF and oligomers play a seminal role in AD (oligomer hypothesis). Thus, the inhibition of the oligomerization of Aβ has been suggested as a possible therapeutic target for the fundamental treatment of AD. We summarize here recent efforts to produce therapeutic drugs targeting Aβ oligomerization. Recently, we found that various compounds such as wine-related polyphenols and rifampicin inhibited the Aβ oligomerizaition and reduced neuronal and synaptic toxicities in vitro and in vivo. Although initial trials of some anti-aggregation agents have failed, they could be key molecules for the development of preventives and therapeutics for AD. | | 2S8-2
Tau oligomers in tauopathy
Takami Tomiyama
Dept Transl Neurosci. Osaka City Univ Grad Sch Med
Tau inclusions are a pathological hallmark of neurodegenerative tauopathies, which includes Alzheimer’s disease (AD), Pick disease, progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Abnormal phosphorylation of tau is the initial step in the pathology. Hyperphosphorylated tau shows a lowered ability to bind microtubules and an increased tendency toward self-aggregation, which leads to intracellular accumulation of tau aggregates resulting in tau tangle formation. Such tau pathology has been suggested to spread in the brain probably by intercellular transfer of pathological tau species. This process includes the secretion of tau aggregates from affected neurons, their internalization into connecting neurons, and the seed-mediated de novo aggregation of naive tau within the cells. The seeds in the propagation were initially proposed to be insoluble tau fibrils, but recent evidence implies that soluble tau oligomers are the real mediator. Several studies have revealed that tau oligomers are neurotoxic, while tau fibrils or tangles do not affect neuronal function. In addition, the levels of tau oligomers in brain soluble fractions and CSF from AD patients were significantly higher than those in age-matched controls. These findings indicate a similarity in the pathological significance between tau oligomers in tauopathy and Aβ oligomers in AD. Notably, passive immunization with tau oligomer-specific antibody into AD model mice has been shown to clear not only tau but also Aβ oligomers and improve mouse memory. This finding suggests that anti-tau oligomer treatment may have a broad therapeutic benefit. Taken together, soluble tau oligomers could be a useful biomarker for as well as suitable target in the prevention and treatment of tauopathy. | | 2S8-3
The importance of α-synuclein oligomers in the pathogensis of Parkinson's disease
Takahiko Tokuda
Department of Molecular Pathobiology of Brain Diseases, Kyoto Prefectural University of Medicine
Parkinson’ s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’ s disease. Although the accumulation of α-synuclein (α-syn) is central to the development of synucleinopathies, the precise pathophysiological mechanism remains uncertain. Among the different species of α-syn, intermediate oligomers/protofibrils are thought to be the major neurotoxic species. Therefore, developing diagnostic and therapeutic strategies that target these species is particularly important. From the viewpoint of biomarker for PD, CSF levels of α-syn oligomers and the ratios of oligomers to total α-syn were found to be substantially higher in patients with PD including those with mild and early-stage disease, and have a sufficient diagnostic ability. Furthermore, soluble α-syn oligomers have been receiving much attention as a molecular basis of the propagation of α-syn pathology in the brain. There is substantial evidence that misfolded α-syn can transfer between cells and can act as a seed that recruits endogenous α-syn, leading to formation of larger aggregates. Furthermore, in some animal models, there is progressive development of α-syn inclusions, starting in the enteric nervous system and then arising sequentially in caudal brainstem and the substantia nigra, which findings recapitulates some aspects of the pathological staging in patients with PD.In this symposium, I will review the central role of α-syn in PD and discuss evidence suggesting that α-syn spreads within the nervous system in a prion-like manner in synucleinopathies, then I will discuss future research directions and their implications for the development of novel biomarkers and therapeutic strategies for PD. | | 2S8-4
Modeling of Human Neurological/Psychiatric Disorders using iPS cells
Hideyuki Okano
Department of Physiology, Keio University School of Medicine
What makes the investigation of human psychiatric/psychiatric disorders so difficult? This could be attributed to the following reasons 1) Diseases model mice do not always recapitulate the pathophysiology of human diseases, 2) It is extremely difficult to investigate what is taking place in vivo at the onset of the disease due to the low accessibility to the pathological foci in the brain, and 3) The responsible neuronal circuits for the phenotype are not identified. In order to overcome these difficulties, we took advantage of iPS cell technologies for modeling human psychiatric/psychiatric disorders.So far, we have established iPS cells from the patients of about 40 human psychiatric/psychiatric disorders and characterized their pathophysiology, including Alzheimer disease, Parkinson disease, ALS, Rett syndrome and Pelizaues-Merzbacher disease. Furthermore, in collaboration with the group of RIKEN BSI and University of Tokyo, we established iPS cells from the schizophrenia patients containing 22q11 deletions. Interestingly, we found that the copy number of a retrotransposon, long interspersed nuclear element-1 (L1), was increased in neurons induced from iPS cells from schizophrenia patients containing 22q11 deletions, indicating that hyperactive retrotransposition of L1 in neurons triggered by genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia. The present study was performed with the approval of ethical committee of the Institute (Approval Number: 20-16-15) according to the Helsinki Declaration. | |
|
|
