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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 Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's 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.

Beta-amyloid (Abeta) deposition and senile plaque-associated astrocytes are common neuropathological features of Alzheimer's disease (AD). Although the molecular mechanisms by which Abeta contributes to the progression of neuropathologic changes have not been entirely established, there is little doubt that the association of Abeta with astrocytes, the predominant cell type in brain, significantly influences exacerbation of the disease. In an effort to identify astrocyte-derived molecules that may be intimately associated with progression of AD, we identified a novel Abeta-induced rat gene, designated Mib, whose human counterpart covers KIAA0233. Mib-transfected C6 cells express Mib protein in the endoplasmic reticulum and endplasmic reticulum-Golgi-intermediate compartment. To evaluate roles of Mib in AD, we investigated its expression in the AD brain. In non-AD brains, Mib mRNA has been detected in neurons but not in quiescent astrocytes. On the contrary, in AD brains, Mib mRNA is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. From these observations, Mib appears to be a novel Abeta-responsive gene that may play a role in astrocyte inflammatory activation around senile plaques in the AD brain.

Fas antigen (CD95) is a cell surface protein that mediates apoptosis. We have investigated the immunohistochemical localization of Fas antigen in postmortem brain tissue from control subjects, patients with Alzheimer-type dementia (ATD), and from a few patients with diffuse Lewy body disease, progressive supranuclear palsy and adrenoleukodystrophy. In all brains, including controls, vascular endothelial cells and residual blood plasma were weakly stained. In ATD brains, senile plaques and a small number of star-like cells were brains of patients with neurological diseases other than ATD. In double immunostaining for Fas and glial fibrillary acidic protein (GFAP), a small number of cells were positive for both antigens. The majority of Fas-positive astrocytes were, however, negative for GFAP. This implies the downregulation of GFAP production in these cells. Doubly labeled astrocytes were also found around senile plaques, suggesting that the Fas immunoreactivity in senile plaques was derived from astrocytic membranes. The results of this study indicate that Fas antigen is expressed by a subset of reactive astrocytes in degenerative neurological diseases. Such astrocytes may undergo the Fas-mediated apoptotic process.

Astrocytes associated with beta-amyloid (Aβ)-deposited senile plaques are a common neuropathological feature of Alzheimer's disease (AD). There is little doubt that the association of Aβ with the major component in the central nervous system cells significantly influences disease progression, however, the molecular mechanisms by which Aβ contributes to the astrocyte-mediated neuropathological changes have not been well established. In an effort to identify astrocyte-derived molecules that may be closely associated with exacerbation of AD, we identified a novel Aβ-induced rat gene, whose mouse counterpart, mitsugumin 29 (MG29), is known to be involved in intracellular Ca2+ homeostasis in skeletal muscle. To evaluate the roles of human MG29 in AD, we investigated its expression in AD brain. In non-AD brains, MG29 mRNA has been detected in neurons, but not in quiescent astrocytes. On the contrary, in AD brains, MG29 is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. Human MG29-transfected cells express the protein in the endoplasmic reticulum and the level of expression is involved in Ca2+-dependent exocytosis mechanisms. Increased MG29 expression in senile plaques-associated activated astrocytes suggests that intracellular Ca2+ turnovers may be changed in these astrocytes. This might be related in sustained Ca2+-dependent exocytosis of various transmitters including glutamate, leading to the acceleration of neurodegeneration in the lesion observed in AD.

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 Alzheimer's 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.

We investigated the cyclin-dependent kinase (Cdk) 5 distribution pattern in diffuse Lewy body disease brains using immunohistochemistry. Cdk5 immunoreactivity was detected in both brainstem-type Lewy bodies (LBs) and cortical LBs. The number of Cdk5-positive LBs was less than that of ubiquitin- or alpha-synuclein-positive LBs, and more than that of phosphorylated neurofilament-positive LBs. Immunoelectron microscopy revealed Cdk5-immunolabeled granulo-filamentous components in LBs and LB-related neurites. These data suggest that Cdk5 may be associated with LB formation.

Telencephalin (TLN) is a cell adhesion molecule expressed in the telencephalon of the mammalian central nervous system. We have investigated immunohistochemically the expression of TLN in human brain tissue from control subjects and patients with Alzheimer's disease (AD). In control brain, neuropil of the gray matter was stained diffusely with the anti-TLN antibody. TLN immunoreactivity was markedly decreased in the brain of AD patients, particularly in the hippocampal formation.

To investigate structural changes in cell membranes of the Alzheimer-type dementia (ATD) brain, we immunostained for GM1 ganglioside which is a major component of the cell membrane. Our results have shown that astrocytic membranes and senile plaques (SPs) have the same immunoreactivity against the monoclonal anti-ganglioside GM1 antibody. Moreover, the astrocytic processes within the SPs were altered and their abnormal membranes seemed to contribute to the formation of SPs.

The distribution of 5-HT-like immunoreactivity in paraformaldehyde-fixed sections of retina, optic nerve and the optic lobe of Octopus vulgaris was studied by both immunofluorescence and avidin-biotin complex (ABC) immunohistochemical methods utilizing polyclonal antibodies to 5-HT. Some immunoreactive serotonin-containing cells were demonstrated in the retinal plexus, optic nerve, the ciliary body and the lens-generating tissue by both methods. An analysis of dissected retina and optic nerve of Octopus vulgaris by high pressure liquid chromatography (HPLC) with an electrochemical detector (ECD) also showed the presence of 5-HT. In the optic lobe, three 5-HT-immunoreactive bands in the plexiform layer of the cortex were clearly immunostained, and in the medulla both the cell islands and the neuropil contained some cells immunostained by both fluorescein isothiocyanate (FITC) and ABC methods. This is the first report on the systemic immunocytochemical visualization of 5-HT-containing cells and/or fibers in the cephalopod visual system.

Using a sensitive double-antibody solid-phase enzyme immunoassay method alpha-melanocyte stimulating hormone-like immunoreactivity (alpha-MSH-LI) was measured in 21 regions of postmortem brains from 8 normal subjects and 5 patients with Alzheimer-type dementia (ATD). In the brains from the normal subjects, the highest concentration of alpha-MSH-LI was found in the hypothalamus. Relatively high concentration were also measured in the locus coeruleus, substantia innominata, substantia nigra, amygdala and medial nucleus of thalamus. alpha-MSH-LI in other regions was approximately 1/100 of the hypothalamic content. This data is consistent with the existence of alpha-MSH in extrahypophyseal regions and indicates its regional distribution in the human brain. In the Alzheimer brains, although the temporal cortex and hippocampus had normal concentrations of alpha-MSH-LI, the cingulate cortex, caudate and substantia nigra showed significantly lower concentrations of alpha-MSH-LI than those of the control brains. This data suggests that further studies of alpha-MSH content in a larger number of ATD brains would be useful.