Norimichi Shirafuji

Periodic synchronous dischargeを呈しCreutzfeldt-Jakob病との鑑別を要した橋本脳症の1例

Here, we report a case of Hashimotos encephalopathy (HE) mimicking Creutzfeldt-Jakob disease (CJD). A 57-year-old man was admitted to our hospital for status epilepticus. He had gradually presented personality change over the last two years. On admission, he was in state of akinetic mutism. He exhibited seizures on the left side of his body, including the face, and intermittent myoclonic movement. Routine laboratory tests showed no abnormalities, including thyroid functions. An EEG study showed typical periodic synchronous discharge (PSD). Brain MRI showed high-intensity areas in the bilateral frontal cortex, thalamus, and right insula on diffusion-weighted imaging (DWI). So, initially, sporadic CJD was suspected. However, there were no abnormalities in the caudate or putamen on MRI. Anti-TG and anti-TPO antibodies, as well as anti-NAE antibody were all positive. He was administered methylpredonisolone pulse therapy. Subsequently, his consciousness levels and EEG and MRI findings markedly improved. So, he was finally diagnosed with HE. HE should be considered in patients with PSD on EEG, even if the patients have typical MRI abnormalities of CJD. Anti-thyroid antibodies should be examined in such patients.

Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization

Increased plasma homocysteinemia is considered a risk factor of dementia, including Alzheimer’s disease (AD) and vascular dementia. However, the reason elevated plasma homocysteinemia increases the risk of dementia remains unknown. A pathological hallmark of AD is neurofibrillary tangles (NFTs) that consist of pathologically phosphorylated tau proteins. The effect of homocysteine (Hcy) on tau aggregation was explored using human neuroblastoma M1C cells that constitutively express human wild-type tau (4R0N) under the control of a tetracycline off system, primary mouse cultured neurons, and by inducing hyperhomocysteinemia in a mouse model of tauopathy (HHCy mice). A wide range of Hcy concentrations (10–1000 µM) increased total tau and phosphorylated tau protein levels. Hcy activated glycogen synthase kinase 3, and cyclin dependent kinase 5, major tau phosphokinases, and inactivated protein phosphatase 2A, a main tau phosphatase. Hcy exhibited cytotoxic effects associated with enhanced activation of caspase. Truncation of tau in the C-terminus, the cleavage site of caspase 3 (i.e., D421, detected by the TauC3 antibody) was also increased. Total tau, phosphorylated tau, as well as C-terminal cleaved tau were increased in the sarkosyl insoluble tau fraction. Hcy also increased the level of tau oligomers, as indicated by the tau oligomer complex 1 (TOC1) antibody that specifically identifies oligomeric tau species, in the tris insoluble, sarkosyl soluble fraction. The levels of TOC1-positive oligomeric tau were increased in brain lysates from HHCy mice, and treating HHCy mice with S-adenosylmethionine, an intermediate of Hcy, reduced the levels of oligomeric tau to control levels. These observations suggest that Hcy increases the levels of phosphorylated tau as well as truncated tau species via caspase 3 activation, and enhanced tau oligomerization and aggregation.

The Implications of Autophagy in Alzheimer’s disease

The pathogenic mechanisms of Alzheimers Disease (AD) involve the deposition of abnormally misfolded proteins, amyloid β protein (Aβ) and tau protein. Aβ comprises senile plaques, and tau aggregates form Neurofibrillary Tangles (NFTs), both of which are hallmarks of AD. Autophagy is the main conserved pathway for the degeneration of aggregated proteins, Aβ, tau and dysfunctional organelles in the cell. Many animal model studies have demonstrated that autophagy normally functions as the protective factor against AD progression associated with intracytoplasmic toxic Aβ and tau aggregates. The upregulation of autophagy can also be favorable in AD treatment. An improved understanding of the signaling pathways that regulate autophagy is critical to developing AD treatments. The cellular and molecular machineries of autophagy, their function in the pathogenesis of AD, and current drug discovery strategies will be discussed in this review.

Efficacy of short questionnaire for screening of early stage of dementia. Trial in Fukui prefecture, Japan

Hamano T1,2, Hayashi K1, Fujita Y3, Matsubara R4, Nagata M5, Ikebata Y6, Ito T,7 Ibe A,8 Sasaki H1, Yamaguchi T1, Enomoto S1, Endo Y1, MD, Ueno A1, Shirafuji N Ikawa M1, Yamamura O1, Nakamoto Y1, Hayashi K1, Yamamura O1, Nakamoto Y1 1Second Department of Internal Medicine, and 2Department of Aging and Dementia, Faculty of Medical Sciences, University of Fukui, Fukui, 3Fujita Neurology Hospital, Fukui, 4Matsubara Hospital, Fukui, 5Nakamura Hospital, Echizen-city, 6Ikebata Hospital, Echizen-city, 7Sukoyaka Silver Hospital, Fukui, 8Ibe Hospital, Echizen-cho, Japan

HYPOPERFUSION-INDUCED TAU HYPERPHOSPHORYLATION EXTENDS TO THE NON-HYPOPERFUSED AREA IN MOUSE BRAIN

Background: Hyperphosphorylation and pathological aggregation of tau and axonal damage is a common feature of many neurodegenerative diseases including Alzheimer’s disease. However, the contribution of cerebral hypoperfusion to tau hyperphosphorylation accompanied by axonal damage remains unclear. Recent study indicates that incident stroke was associated with acute decline in cognitive function and also accelerated and persistent cognitive decline. We hypothesized that hypoperfusion-induced tau hyperphosphorylation may propagate to the non-hypoperfused area. Methods: Adult C57Bl/6 male mice were subjected to unilateral common carotid artery occlusion (UCCAO), which induces chronic cerebral hypoperfusion in the hemisphere ipsilateral to UCCAO; a mouse model of vascular dementia with white matter lesions. The brains of the mice were analyzed by immunohistochemistry and immunoblotting to detect phosphorylated tau and axonal changes after the surgery. Results:Hosphorylated tau was increased in cortical neurons in the hemisphere ipsilateral to the UCCAO. Moreover, phosphorylated tau was increased in the contralateral hemisphere with a difference in the time course. White matter rarefaction was observed in the corpus callosum, where the number of Iba-1-immunopositive microglia and GFAP-immunopositive astroglia increased after the surgery. The number of SMI311-immunopositive fibers decreased in the ipsilateral corpus callosum, which indicated axonal damage within the white matter lesion after chronic cerebral hypoperfusion. Conclusions:The results indicate that cerebral hypoperfusion induces tau hyperphosphorylation accompanied by axonal damage in adult mice. Moreover, indicating that there is interhemispheric propagation of hypoperfusion-induced tau hyperphosphorylation in mouse brain.

Donepezil reduces phosphorylation levels of tau protein in a cellular model of tauopathy

Background:Neurofibrillary tangle (NFT) is the pathological hallmark of Alzheimer’s disease. Hyperphosphorylated tau is a major constitute of NFT. Donepezil hydrochloride is a potent acetylcholinesterase inhibitor, which is widely used for improvement of the cognitive function in AD, as well as dementia with lewy bodies. Recently, it was disclosed that AD patients who recieved donepezil for a long period showed the slowing of disease progression. However, the mechanisms are not yet clear. Methods: M1C cells that express wild-type human brain tau (4R0N) via Tetracycline Off induction (Hamano et al., EurJ Neursci 2008; Hamano et al., Neurobiol Aging 2012) were treated with 0.1 to 10 m M of donepezil for 24 h. The levels of total and phosphorylated tau were examined before and after donepezil treatment by Western blotting and immunocytochemistry. Results:We found that 0.1 to 10 m M of donepezil reduced phosphorylated tau levels by Western blot analysis, as well as an immunocytochemical study. Donepezil treatment also inactivated GSK3 b, which is one of the tau kinases, via the activation of Akt. Donepezil did not show cytotoxic effects. Conclusions: It was suspected that donepezil decreased phosphorylation levels of tau protein via the inactivation of GSK3. Although the mechanisms responsible for the reduction of phosphorylation levels of tau protein by donepezil require further examination, this report sheds light on possible therapeutic approaches to tauopathy.

Erratum: Pioglitazone decreases the phosphorylated and total tau protein (Alzheimer's and Dementia)

In Fig. 4.6 the units of the Dwell time, horizontal axis, should be seconds. In Fig. 4.7b the units of the Access frequency, vertical axis, should be arbitrary instead of min−1. The actual switching frequency is approx. 5 min−1. In the rst paragraph of the Outlook the following paper regarding the GA cross-linking by Ilioaia et. al. should be cited: Ilioaia, C., Johnson, M. P., Horton, P. and Ruban, A. V. Induction of E cient Energy Dissipation in the Isolated Light-harvesting Complex of Photosystem II in the Absence of Protein Aggregation. Journal of Biological Chemistry, 2008, 283, 29505

Delusions of theft in patients with dementia

Background: Laminaria japonica , an edible brown seaweed, has long been utilized since ancient times as an important food resource to promote maternal health in Pacific and Asian countries. Due to its high contents of dietary fiber, minerals, carbohydrates, and protein, L. japonica has recently attracted much attention for its bioactive materials and nutraceutical qualities. Methods: The present study examined the effects of desalted Laminaria japonica (D LJ) on learning and memory function and cholinergic neuron activity in trimethyltin (TMT) induced memory deficits rats.After TMT injection (8mg/kg, i.p.), rats were administered with saline or D LJ (10 and 50mg/kg, p.o.) daily for 21 days. The cognitive improving effects of D LJ on TMT-induced amnesic rats were investigated by assessing the Morris water maze test and by performing choline acetyltransferase (ChAT) immunohistochemistry.Results: In theMorris water maze, TMT treated group produced impairment in escape latency to find the platform. However, DLJ treated groups were significantly recovered the impairment of memory compared to the control group (on the 2nd and 4th day (P <0.05)). Consistent with behavioral data, DLJ group was significantly increased ChAT-ir neurons in the midial striatum compared to the control group (P <0.01). Conclusions: In conclusion, administration of D LJ improved spatial learning and memory. These results suggest that D LJ may be useful for the cognitive improvement via regulation of cholinergic marker enzyme activity.

Pitavastatin decreases tau levels via the inactivation of Rho family small G proteins

a mouse one array whole genome DNA microarray we investigated the global gene expression profile in the hippocampi obtained from 3xTgAD (expressing mutant human APP, PS1, and tau), PS1KI (expressing human mutant PS1, but not developing any AD-like pathology), and WT mice at 3 and 12 months of age (m.o.a.). Hierarchical clustering analysis was performed by using Cluster 3.0 and treeview software. Data were also analyzed with the Ingenuity Pathways Analysis (IPA) in order to achieve a classification of the results on the basis of their biological functions and disclose functional networks and/or pathways. Results: Our study investigated, with clustering analysis, the expression profile of 3xTg-AD and PS1KI mice in comparison to WT mice at 3 m.o.a as well as WT mice at 12 m.o.a. vs WT mice at 3 m.o.a. The analysis revealed that 3xTG AD mice at 3 m.o.a. and WT mice at 12 m.o.a undergo the selective upregulation of 63 transcripts that are instead found down regulated in PS1 at 3 m.o.a. The IPA analysis of the upregulated transcripts indicated that these genes were involved in: Amyloid plaques formation (APPB2, LPL) Calcium signaling (TRPM3, JAK3), Potassium channel expression (KNEC2), Neuron development and differentation (DULLARD, FGF10, JHDM1D) Nerve injury (FLT3), Neurodegenaration (NCAM, IRF1, TMEM1106B), Apoptosis (FAIM3, CSTB, ST6GAL2, TRIAP1, IRF1), Neurite formation (Neu4), Senescence (HDAC8), Cell cycle progression (HAUS8, NOL8, SNAPC2), inflammation (GPR182) and the expression of Olfactory receptors (OLFR731, OLFR958). Conclusions: We find that the over-expression of AD-related genes such as mutant APP, PS1, and tau in 3xTg-AD mice up regulate early on the expression of genes that are upregulated by aging in WT mice at 12 m.o.a. These genes are critical for amyloid dismetabolism, neuronal survival, calcium homeostasis, inflammation and aging, suggesting that the pro-AD environment present in the 3xTg-AD animal accelerates the expression of some genes that are modulated by aging. These results may help to unravel the role of gene expression in both AD progression and/or senescence.