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Yanagisawa K.,Center for Development of Advanced Medicine for Dementia
Glycoconjugate Journal | Year: 2015

Assembly and deposition of amyloid ß-protein (Aß) is an invariable and fundamental event in the pathological process of Alzheimer's disease (AD). To decipher the AD pathogenesis and also to develop disease-modifying drugs for AD, clarification of the molecular mechanism underlying the Aß assembly into amyloid fibrils in the brain has been a crucial issue. GM1-ganglioside-bound Aß (GAß), with unique molecular characteristics such as having an altered conformation and the capability to accelerate Aß assembly, was discovered in an autopsied brain showing early pathological changes of AD in 1995. On the basis of these findings, it was hypothesized that GAß is an endogenous seed for amyloid fibril formation in the AD brain. A body of evidence that supports this GAß hypothesis has been growing over this past 20 years. In this article, seminal GAß studies that have been carried out to date, including recent ones using unique animal models, are reviewed. © 2015 Springer Science+Business Media New York. Source


Kimura N.,Center for Development of Advanced Medicine for Dementia
International Journal of Molecular Sciences | Year: 2016

Alzheimer’s disease (AD) is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. Although genetic studies show that β-amyloid protein (Aβ), the major component of SPs, is the key factor underlying AD pathogenesis, it remains unclear why advanced age often leads to AD. Interestingly, several epidemiological and clinical studies show that type II diabetes mellitus (DM) patients are more likely to exhibit increased susceptibility to AD. Moreover, growing evidence suggests that there are several connections between the neuropathology that underlies AD and DM, and there is evidence that the experimental induction of DM can cause cognitive dysfunction, even in rodent animal models. This mini-review summarizes histopathological evidence that DM induces AD pathology in animal models and discusses the possibility that aberrant insulin signaling is a key factor in the induction of AD pathology. © 2016 by the author; licensee MDPI, Basel, Switzerland. Source


Shimada H.,Center for Development of Advanced Medicine for Dementia
Current Aging Science | Year: 2012

Gait disorders have been identified as one of the most influential physical impairments associated with deteriorationin daily living activities among the elderly. A better understanding of the mechanisms responsible for gait disorders is important for developing intervention strategies for the elderly. In recent years, positron emission tomography (PET)and [ 18F]fluorodeoxyglucose (FDG) have been used to monitor glucose uptake by skeletal muscle during exercise. This review discusses recent studies in which FDG PET has been used to measure muscular glucose uptake, differences between young adults and the elderly in muscular glucose uptake during walking, and the usefulness of FDG PET for determining the effects of exercise intervention in the elderly. © 2012 Bentham Science Publishers. Source


Takashima A.,Center for Development of Advanced Medicine for Dementia
Frontiers in Molecular Neuroscience | Year: 2012

In Alzheimer's disease (AD), tau hyperphosphorylation and neurofibrillary tangle (NFT) formation are strongly associated with dementia, a characteristic and early feature of this disease. Glycogen synthase kinase 3β (GSK-3β) is a pivotal kinase in both the normal and pathological phosphorylation of tau. In the diseased state, hyperphosphorylated tau is deposited in NFTs, the formation of which, drive the disease process. GSK-3β which is also involved in long-term depression induction, interacts with tau to inhibit synaptic long-term potentiation. Strong lines of evidence suggest that the activation of GSK-3β is responsible for the memory deficits seen in both advanced age and AD. In this review, we will focus on the role of GSK-3β in brain function, particularly in memory maintenance. We will examine human and mouse studies which suggest a role for GSK-3β in memory maintenance and the eventual development of memory deficits. © 2012 Takashima. Source


Yanagisawa K.,Center for Development of Advanced Medicine for Dementia
Nihon rinsho. Japanese journal of clinical medicine | Year: 2012

A decrease in the concentration of amyloid beta-protein-42 and an increase in that of tau or phosphorylated tau in addition to volumetry on MRI and amyloid imaging by PET are available biomarkers. However, we need better biomarkers to detect very early stage of Alzheimer disease to develop disease modifying drugs, which should be used 10 or 15 years prior to emergence of clinical symptoms. In terms of biomarkers for other dementing neurodegenerative diseases, including synucleinopathies such as dementia with Lewy bodies and multiple system atrophy, and tauopathies such as progressive supranuclear palsy, corticobasal degeneration, synuclein, TDP-43, progranulin and tau may be candidate proteins for possible biomarkers for these diseases. Source

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