Amyloid-βpeptide (Aβ) is the major component of senile plaques deposited in the brains of patients with Alzheimer disease (AD). Several lines of evidence suggest that the accumulation of A βis linked to the pathogenesis of AD. A βis derived from amyloid-βprecursor protein (APP) that is sequentially cleaved by two aspartate proteases, β- and γ- secretases. Advances in basic research and observational study implicate that that drugs that inhibit or modulate the proteolytic activity of these secretases could provide a disease- modifying therapy against AD as pre- emptive medicine. In addition, evolutional genome sequencing technologies reveal several genetic risk factors, which may impact on the onset of AD. In this review, I will discuss about recent status regarding the development of therapeutics for AD.

View full abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects upper and lower motor neurons. TAR DNA-binding protein 43 kDa (TDP-43), an RNA-binding protein redistributes from nucleus to cytoplasm and forms aggregates, which are the histopathological hallmark of sporadic amyotrophic lateral sclerosis, in affected motor neurons. TDP-43 in the aberrant inclusion is known to be hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re- distribute from nucleus to cytoplasm or neurite. Ethacrynic acid (EA), which increases cellular oxidative stress through glutathione depletion, induces TDP-43C-terminal phosphorylation, insolubilization, C-terminal fragmentation, and cytoplasmic distribution in cultured neuronal cells and primary cortical neurons, suggesting that the loss of nuclear TDP-43 may play a role in the pathogenesis of ALS. Motor neuron- specific knock out of TDP- 43 results in progressive weight loss and motor impairment together with degeneration of large motor axon, grouped atrophy of the skeletal muscle, and denervation in the neuromuscular junction. These findings suggest that loss-of-function of TDP-43 appears to contribute to the pathogenesis of ALS.

View full abstract

The efficiency of DNA damage repair declines with aging similarly to other cellular functions, and the decline is faster in neurodegenerative diseases. We suppose this is one of the molecular bases by which aging promotes neurodegeneration. Especially, neurons are vulnerable to DNA damage because they have no opportunity of cell division. We have found that the causative proteins of polyglutamine disease inhibit HGMB1/2, which regulate the architecture of DNA, and therefore DNA double strand break is increased. Additionally, we have reported that Ku70 and VCP, both of which have central functions in DNA double strand break repair, are disturbed by polyglutamine proteins. Also, neurodegenerative diseases including ataxia- telangiectasia, early- onset ataxia with ocular motor apraxia and hypoalbuminemia / ataxia with oculomotor apraxia type 1, xeroderma pigmentosum, and Cockayne syndrome are caused by mutations in DNA repair- related genes. These studies suggest that DNA damage is common pathology of various neurodegenerative diseases, and that aging, more than diseases, can be controlled by improving the repair of DNA damage.

View full abstract

Fatigue is defined as a condition or phenomenon of declined ability and efficiency of mental and/or physical activities caused by excessive mental or physical activities, or diseases or syndromes. Acute fatigue is a normal condition that disappears after a period of rest ; in contrast, chronic fatigue does not disappear after an ordinary rest. Chronic fatigue impairs daily activities and contributes to various medical conditions and death. In addition, many people complain of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from biochemical, neuroimaging, and molecular imaging studies related to the neural and molecular mechanisms underlying chronic fatigue. We propose that repetitive and prolonged overwork and/or stress cause neural damage of a facilitation system as well as central sensitization and classical conditioning of an inhibition system. We also propose a new treatment strategy for chronic fatigue on the basis of its underlying neural/molecular mechanisms.

View full abstract

We have developed various animal models of fatigue. Here, two types of models using rats are introduced : one is a model of central fatigue obtained by excessive depolarizing stimuli to the central nervous system ; another is that of immunological fatigue obtained by intraperitoneal injection of polyriboinosinic : polyribocytidylic acid (poly I : C) , double- strand RNA, which mimics viral infection. In the central fatigue model, we introduced cortical spreading depression, the propagation of neuronal membrane depolarization throughout the cerebral cortex. Prostaglandins (PG) including PGD2 were produced by COX- 2 expression in neurons in the cortex following cortical spreading depression. In such a model, the amount of non- REM sleep, but not of REM sleep, increased subsequently for several hours in the animals, and the increase was completely attenuated by application of NS- 398, a COX- 2 inhibitor. Such a system is thought to relieve excessive brain activity by inducing resting behavior and non- REM sleep. In the immunological fatigue model, intraperitoneal administration of poly I : C induced transient fever and suppression of locomotor activity in rats. We have demonstrated that interleukin (IL) - 1 βexpression was up- regulated in various brain regions, and that intracerebroventricular infusion of IL- 1 receptor antagonist significantly attenuated the poly I : C- induced fatigue- like behavior. The balance of IL- 1 βand the endogenous antagonist in the brain possibly regulates immunological fatigue sensation.

View full abstract

Human herpesvirus (HHV-) 6 is capable of establishing a lifelong latent infection of their host, is reactivated frequently. We are studying the molecular mechanism of latency and pathogenesis of HHV-6, and find SITH-1 a novel latent protein of HHV-6 which associate with mood disorders. Additionally we are trying to apply HHV-6 and HHV-7 to the tools for studying the mechanism of fatigue and to the viral vector for gene therapy. Fatigue is an indispensable bio-alarm to avoid the exhaustive state caused by severe stresses and overwork, which may also induce a variety of diseases. We have investigated the molecular mechanism of HHV-6 and HHV-7 reactivation that was known to be stimulated by fatigue, and identified the molecule that can induce viral reactivation during fatigue. Using the knowledge of herpesvirus reactivation, we have developed a method for measuring accumulation of fatigue by determining the amount of a HHV-6 and HHV-7, which is reactivated, and released into saliva.

View full abstract

Nowadays, there are lots of papers showing the relationship between the chronic fatigue syndrome (CFS) and functional somatic syndromes (FSS) . The CFS is an operational concept proposed by the Centers for Disease Control and Prevention in 1988 to clarify the unknown etiology of the syndrome characterized by the sensation of abnormally prolonged fatigue, pain, loss of thinking, depression, and sleep disturbance. On the other hand, the FSS has been reported, before the rise of concept of CFS, to refer to the presence of physical symptoms, unattributable to organ pathology, which disturb the daily activities. In 1999, Wessely S et al. reviewed the concept and importance of FSS and syndromes such as irritable bowel syndrome and CFS. They showed that there are similarities in their symptoms, case definitions, patients’ sex, outlook, and responses to treatments. They proposed that the existing definition of these syndromes in terms of specific symptoms is of limited value, and that a dimensional classification is likely to be more productive. In this paper, we summarise the overview of CFS and FSS, and introduce our recent hypothesis focusing on the pathophysiology of CFS.

View full abstract

The acoustic startle response (ASR) is a useful neurophysiological measurement in translational research. People with ASD is known to have enhanced auditory perception, however, ASR to weak stimuli in ASD is not investigated well. Thus, the basic profile of ASR, including response to weaker stimuli, might be atypical in ASD, and, close examination of the profile is necessary in order to evaluate ASR. Here, we investigated ASR in 10 Japanese children with ASD and 34 without ASD. The electromyographic activity of the left orbicularis oculi muscle to pulse stimuli of 65 to 115 dB SPL, in increments of 5 dB, was measured to evaluate ASR. Average eyeblink magnitude, average peak startle latency of ASR for each acoustic stimuli intensity was evaluated. Quantitative autistic traits were assessed with the Social Responsive Scale (SRS) to analyze the relationship between startle measures. Magnitude of ASR to weak stimuli (70dB) , was greater in ASD individuals, and Peak startle latency was prolonged in ASD. These startle measures were associated with several subscale scores of SRS. Comprehensive investigation of ASR, including the magnitude of startle responses to weak stimuli and peak startle latency, might increase understanding of the neurophysiological impairments underlying ASD.

View full abstract

One of the most characteristic impairments in social communication in pervasive developmental disorders (PDD) is the failure to perceive and respond to non-verbal conversational cues such as facial expression. We found out that healthy subjects had significantly increased oxyHb changes during a processing task of fearful expression compared to happiness in the prefrontal cortex (PFC) and found significant correlations between oxyHb change in PFC and Autism-Spectrum Quotient score using near-infrared spectroscopy (NIRS). Moreover, we showed that 14 patients with PDD had significantly reduced oxyHb changes in PFC during a processing task of fearful expression compared to 14 age-and sex-matched healthy controls. NIRS could be one of the most powerful tools for PDD research, because it has advantages in convenience, non- invasiveness and less of psychological and physical burden.

View full abstract

Although it has been often reported that the dysfunctional mirror neuron system (MNS) hypothesis in patients with autistic spectrum disorder (ASD) using EEG and MEG, targeting mu rhythm suppression during action observation/execution, the results were quite controversial. In this study, we explored neural activity related to the MNS in patients with ASD, focusing on power increase in the beta frequency band after observation and execution of movements, known as post-movement beta rebound (PMBR). During the MEG recordings, the subjects were asked to observe and later execute object-related hand actions performed by an experimenter. Although both groups exhibited pronounced PMBR exceeding 20% when observing and executing actions with a similar topographic distribution of maximal activity, significantly reduced PMBR was found only during the observation condition in the patients relative to controls in cortical regions within the MNS, namely the sensorimotor area, premotor cortex and superior temporal gyrus. These results support the notion of a dysfunctional execution/observation matching system related to MNS impairment in patients with ASD.

View full abstract

Autism spectrum disorders (ASD) appear in infancy and early childhood, causing delays or impairments in social interaction, communication, and a restricted range of interests. With recent developments in neuroimaging methods, the accumulated evidence suggests that aberrant brain connectivity reflect important aspects of network dysfunction associated with the pathophysiology of ASD. To gain insight into the development of this network dysfunction, it is necessary to study the pathophysiology in younger children with ASD, as aberrant development of white matter pathways may appear in infant stage. However, under conscious conditions, it has been challenging to measure brain functional connectivity in young children with ASD children using creditable methods as they are not always cooperative and persevering. We have recently reported the aberrant brain functional connectivity under conscious conditions in pre- school children with ASD. In our recent studies, we developed the child custom- sized MEG system in which sensors are as close to the whole head as possible for optimal recording even in young children, which otherwise would have been difficult with a conventional adult- sized MEG system. This is a unique and useful technique for young children that can provide measures of cortical neural activity on a millisecond timescale. By obtaining non- invasive measurements with a child custom- sized MEG, we have demonstrate an aberrant brain functional lateralization in conscious preschool children with ASD.

View full abstract

Individuals with autism spectrum disorder (ASD) have not only limitations in social-communication skills and imagination abilities but also motor coordination and sensory processing problems. The brain dysfunction related to sensory processing problems and motor problems in children with ASD has not been clarified, nor have medical treatments been established. Since sensory processing and motor problems affect adaption to daily living, we must elucidate the mechanism of brain dysfunction related to sensory processing and motor problems. Treatments and support methods for individuals with ASD should also be developed. This article describes the current state of motor and sensory processing problems in children with ASD, and rehabilitation approaches that support them.

View full abstract