Takashi Togo

Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies

TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimers disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinsons disease, Picks disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or alpha-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with alpha-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.

Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases

We investigated the occurrence of T cells in the brain parenchyma of Alzheimers disease (AD), non-AD degenerative dementias and controls by semi-quantitative analysis of immunohistochemically stained tissue sections. In all cases, we found at least some T cells. The number of T cells was increased in the majority of AD cases compared with other cases. The phenotype of T cells in the AD brain indicates that they are activated but are not fully differentiated. Antigen-triggered clonal expansion is not likely to take place. Local inflammatory conditions might cause accumulation and activation of T cells in the AD brain.

Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases.

We have investigated immunohistochemically the expression of CD40 in post-mortem human brain tissues. In control brain, the blood vessels were stained weakly for CD40. Vascular expression of CD40 was enhanced in the lesions of Alzheimers disease and some other neurological diseases. In such diseases, reactive microglia were also positive for CD40. The results of this study suggest that CD40 expression by microglia is up-regulated upon a variety of brain insults and is not limited to lesions with amyloid beta-protein deposits.

Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia.

Although treatment with antipsychotics, particularly olanzapine and clozapine, has been implicated in weight gain and higher incidence of diabetes, the mechanism of these adverse reactions remains unclear. The purposes of this study were to explore the early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin, three recently identified hormones that play crucial roles in the regulation of energy balance and glucose metabolism. Thirteen patients with schizophrenia who had not received any medication in the 4 weeks prior to this study were included. The patients received olanzapine at an average dose of 14.5mg/day. Serum levels of ghrelin, adiponectin, leptin and insulin, as well as weight and fasting glucose, were investigated at the baseline and at 4 weeks. Serum ghrelin levels had decreased (p 0.03) and leptin had increased (p 0.02), while adiponectin and insulin levels had not significantly changed at Week 4 (p 0.29 and p 0.25, respectively). Weight had increased (p 0.01), while fasting glucose had not significantly changed (p 0.46). These findings suggest that ghrelin levels decrease and leptin levels increase after initiation of olanzapine therapy. Weight gain is also considered to be an early change, while change in insulin sensitivity is not an early change of treatment with olanzapine. Further large-scale and longitudinal studies are warranted to elucidate metabolic changes involving ghrelin, adiponectin, leptin and insulin and their impact on weight and glucose metabolism during treatment with olanzapine and other antipsychotics.

Nitric oxide pathways in Alzheimer's disease and other neurodegenerative dementias

Abstract Nitric oxide (NO) is an enzymatic product of nitric oxide synthase (NOS). NO has significant physiological functions and an increasing body of evidence suggests that NO pathways are implicated in a number of neurological disorders, including Alzheimers disease (AD) and other neurodegenerative dementias. NO is continuously released by endothelial cells in the vascular system, whereas advanced age in the presence of vascular risk factor causes a decrease in cerebral blood flow, involving microvasculopathy with impaired NO release, which in turn results in regional metabolic dysfunction. This finding suggests that vascular pathology plays a crucial role in the pathogenesis of so-called neurodegenerative dementias. Inflammatory responses are commonly found in the brain under a variety of neurodegenerative dementias, including AD and dementia with Lewy bodies, in which up-regulation of NOS expression, suggesting overproduction of NO, is found in neurons and glia. NO is thought to be involved in such neuroinflammation due to its free radical properties, which compromise cellular integrity and viability via mitochondrial damage. Further studies to elucidate NO pathways in neurodegenerative dementias could lead to a better understanding of their pathogenesis and improved therapeutic strategies, and therefore are certainly warranted.

Prolyl-isomerase Pin1 Accumulates in Lewy Bodies of Parkinson Disease and Facilitates Formation of α-Synuclein Inclusions

Parkinson disease (PD) is a relatively common neurodegenerative disorder that is characterized by the loss of dopaminergic neurons and by the formation of Lewy bodies (LBs), which are cytoplasmic inclusions containing aggregates of α-synuclein. Although certain post-translational modifications of α-synuclein and its related proteins are implicated in the genesis of LBs, the specific molecular mechanisms that both regulate these processes and initiate subsequent inclusion body formation are not yet well understood. We demonstrate in our current study, however, that the prolyl-isomerase Pin1 localizes to the LBs in PD brain tissue and thereby enhances the formation of α-synuclein immunoreactive inclusions. Immunohistochemical analysis of brain tissue from PD patients revealed that Pin1 localizes to 50–60% of the LBs that show an intense halo pattern resembling that of α-synuclein. By utilizing a cellular model of α-synuclein aggregation, we also demonstrate that, whereas Pin1 overexpression facilitates the formation of α-synuclein inclusions, dominant-negative Pin1 expression significantly suppresses this process. Consistent with these observations, Pin1 overexpression enhances the protein half-life and insolubility of α-synuclein. Finally, we show that Pin1 binds synphilin-1, an α-synuclein partner, via its Ser-211-Pro and Ser-215-Pro motifs, and enhances its interaction with α-synuclein, thus likely facilitating the formation of α-synuclein inclusions. These results indicate that Pin1-mediated prolyl-isomerization plays a pivotal role in a post-translational modification pathway for α-synuclein aggregation and in the resultant Lewy body formations in PD.

Serum ghrelin concentrations in patients receiving olanzapine or risperidone

RationaleAlthough enhanced appetite and weight gain are potential side effects of treatment with antipsychotic agents, particularly olanzapine and clozapine, the mechanism is poorly understood.ObjectivesTo test the hypothesis that ghrelin, a gastrointestinal hormone that enhances appetite, is involved in increased food intake and weight gain during treatment with antipsychotics.MethodsSerum ghrelin concentrations were investigated in schizophrenic patients receiving olanzapine or risperidone, and in healthy volunteers.ResultsSerum ghrelin concentrations did not increase, but rather decreased, in patients treated with olanzapine or risperidone in comparison with healthy volunteers. No significant difference was found in serum ghrelin concentration between patients treated with olanzapine and risperidone.ConclusionsOur results indicate that ghrelin is not a direct cause of increased food intake and weight gain during treatment with olanzapine or risperidone, whereas ghrelin is associated with metabolic change in patients receiving these agents.

Dementia with Lewy bodies from the perspective of tauopathy

Abstract. We immunohistochemically investigated the prevalence and pattern of phosphorylated tau accumulation in neurons and glia in 46 cases of dementia with Lewy bodies (DLB). Tau-positive neurons composed of neurofibrillary tangles (NFT) and pretangle neurons were found in the hippocampal area in all 46 cases, although the ratio of pretangle neurons in tau-positive neurons was higher in the cases showing low NFT stages. Tau-positive astrocytes were found in the periventricular area in 18 of 46 cases, and partly represented argyrophilic thorn-shaped astrocytes. In contrast, tau-positive oligodendroglia were found in the subcortical white matter in 9 of 46 cases, and represented argyrophilic coiled bodies. Tau-positive argyrophilic grains were found in the hippocampal area in the same cases as those with coiled bodies. The 9 cases with tau-positive coiled bodies and grains were included in the 18 cases with tau-positive astrocytes, and showed larger proportions in the low NFT stages than the 46 cases with tau-positive neurons. Tau-positive neurons were positive both to anti-three-repeat (3R) and -4R tau-specific antibodies, while tau-positive astrocytes, coiled bodies and grains were predominantly positive to anti-4R tau-specific antibody. These tau-positive structures were negative to anti-α-synuclein antibody. These findings suggest that the tau accumulation in DLB represents both tau-positive neurons with all six tau isoforms and tau-positive astrocytes, coiled bodies and grains with the 4R tau isoform, and that the different cytoskeletal abnormalities form a link between some neurodegenerative dementing disorders including DLB.

Investigation of Lewy pathology in the visual pathway of brains of dementia with Lewy bodies

We examined 19 autopsied cases of dementia with Lewy bodies (DLB) using pathological and alpha-synuclein-immunohistochemical methods, and investigated Lewy pathology in the primary visual pathway (lateral geniculate body and Brodmanns area 17), secondary visual pathway (pulvinar, Brodmanns areas 18 and 19, and inferior temporal cortex), amygdala and substantia nigra, to clarify the relationship between visual misidentification and Lewy pathology in the visual pathway. Consequently, the secondary visual pathway revealed significantly severer Lewy pathology than the primary visual pathway, suggesting that the degeneration of the secondary visual pathway induces dysfunction in the recognition of objects shape and color. In addition, the amygdala revealed significantly severer Lewy pathology and neuronal loss than the primary and secondary visual pathways, suggesting that the degeneration of the amygdala, which receives the afferent connections from the substantia nigra, fails to modulate the visual processing according to cognition and emotion. These findings suggest that Lewy pathologies in the secondary visual pathway and amygdala may cause the dysfunction of the visuo-amygdaloid pathway and participate in visual misidentification in DLB patients. In addition, we compared Lewy pathology between cases with and without visual hallucinations, and showed no significant differences between the two groups.

Glial involvement in the degeneration process of Lewy body-bearing neurons and the degradation process of Lewy bodies in brains of dementia with Lewy bodies

Glial involvement in the degeneration process of Lewy body (LB)-bearing neurons and the degradation process of LBs in the cerebral cortex and amygdala in brains of dementia with Lewy bodies was investigated immunohistochemically. HLA-DR-positive microglia frequently extended their processes to degenerated neurons with alpha-synuclein-positive LBs, while some GFAP-positive astroglial processes attached to weakly alpha-synuclein-positive extracellular LBs. Some intracellular LBs were immunoreactive to anti-C4d antibody, and these LB-bearing neurons were involved by activated microglia. About half of the intracellular LBs were immunoreactive to anti-chromogranin-A (CGA) antibody, and most of CGA-positive LB-bearing neurons were surrounded by microglia. Although we could find no evident participation of TNF-alpha, a candidate cytokine that is up-regulated by microglia following CGA stimulation, in the degeneration process of LB-bearing neurons, some intracellular LBs were immunoreactive to the antibody to NF-kappaB, a transcriptional factor activated by cytokines. These findings suggest that microglia participate in the degeneration process of LB-bearing neurons via varying immunogenic elements including complement proteins, CGA and probably some cytokines, and that astroglia participate in the degradation process of LBs.