Tissue transglutaminase is not a biochemical marker for Alzheimer's disease.

Typical hallmarks of Alzheimer's disease (AD) are pathologic deposits in cortical and subcortical regions consisting of self-aggregated proteins such as amyloid-beta (Aß) or tau. Tissue transglutaminase (tTG) catalyses calcium-dependent cross-linking between proteins (transamidation) resulting in protease-resistant isopeptide bonds. Because of this ability, tTG was suspected to participate in AD pathogenesis. Aß and tau can be cross-linked by tTG in vitro. In AD neocortex, messenger RNA expression of tTG is increased. However, data on transamidation in AD specimens--activity of not only tTG but also other transglutaminases--are contradictory. The aim of our study was to investigate if tTG is involved in AD development and may be useful as biomarker for AD. We studied human brain samples for tTG concentration, tTG localization, and transamidation activity and cerebrospinal fluid (CSF) for tTG content by novel sensitive and highly specific methods. Neither tTG concentration nor transamidation was increased in AD brain homogenates. Immunohistologically, we found no colocalization of tTG in neocortex sections with tau or Aß deposits but with blood vessels. Only in rare cases, tTG was detectable in CSF samples. This could be attributed to liberation from erythrocytes. Our data contradict the view that tTG is a potential biochemical marker for AD.

Transglutaminase 2: a novel autoantigen in canine idiopathic central nervous system inflammatory diseases.

Necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE) and granulomatous meningoencephalomyelitis (GME) are common idiopathic inflammatory central nervous system (CNS) diseases with unknown etiology in dogs. We previously showed that IgG autoantibodies in the cerebrospinal fluid (CSF) of NME cases reacted to unknown brain proteins as well as to glial fibrillary acidic protein (GFAP). In the present report, we evaluated the autoantibodies against transglutaminase2 (TG2) in the canine CNS diseases. CSF samples obtained from dogs with NME (n=19), NLE (n=7), GME (n=11) and miscellaneous CNS diseases (n=12) were subjected. CSFs from 20 healthy dogs were used as controls. Indirect fluorescent antibody test on the canine cerebrum revealed astrocyte-binding IgG in the CSF of NME. After absorption of the CSF with bovine GFAP, the CSF still possessed the reactivity to astrocytes. Double-color staining showed clear colocalization of the autoantibodies and anti-human TG2 rabbit polyclonal IgG. An immunoblot assay against human recombinant TG2 revealed anti-TG2 IgG in the CSF from dogs with NME, NLE and GME. The CSF of canine idiopathic encephalitis cases, notably of NME, tended to show high ELISA OD values against human recombinant TG2 compared to healthy controls. The presence of anti-TG2 autoantibodies in the CSF may contribute to the elucidation of the etiology of canine NME, NLE and GME.

The influence of psychotropic drugs on cerebral cell death: female neurovulnerability to antipsychotics.

Tissue transglutaminase (tTG) is a marker for apoptosis, and its protein level is known to be increased in post-mortem Alzheimer's and Huntington's disease brains. tTG is increased in the cerebrospinal fluid of patients with Alzheimer's disease. However, the influence of psychotropic medication on acute cell death has not been studied so far in vivo, although some experiments performed in vitro suggest that antipsychotic drugs are neurotoxic. The protein level of tTG was examined in the cerebrospinal fluid obtained from 29 patients under neuroleptic medication in the last 24 h before lumbar puncture (eight patients diagnosed with Alzheimer's disease and 21 patients with other neurological diseases), and compared with those from 55 patients without antipsychotic medication (25 Alzheimer's patients and 30 others). In addition, the influence of several other psychotropic drugs on apoptosis was analysed. A significant influence (P<0.01) of antipsychotic drugs for both the Alzheimer's and the non-Alzheimer's group was found with respect to tTG protein levels in cerebrospinal fluid. By contrast to the male subgroups, the female groups showed a strong influence of neuroleptics on cerebral cell death. Surprisingly, atypical antipsychotics did not differ from typical neuroleptics in neurotoxicity. By contrast, no influence of antidepressants, cholinesterase-inhibitors, nootropics, tranquilizers and tramadol on cerebral cell death was found. The results suggest that typical and atypical antipsychotic drugs may induce cerebral cell death, especially in female patients. Subjects with Alzheimer's disease might be even more vulnerable to any antipsychotic. Therefore, subsequent research should aim to identify atypical neuroleptics without neurotoxicity. A limit on the use of first- and second-generation antipsychotics in elderly patients is proposed. Finally, the possible connection between the observed increased cerebral cell death and tardive dyskinesia, the most threatening side-effect in antipsychotic therapy, is discussed.

Elevated concentration of cerebrospinal fluid tissue transglutaminase in Parkinson's disease indicating apoptosis.

Tissue transglutaminase (tTG) is activated during the apoptotic cell death cascade and plays a key role in the formation of apoptotic bodies. We found significant elevation of tTG concentration in the cerebrospinal fluid (CSF) of 54 patients with Parkinson's disease (PD) compared with that measured in 34 control subjects, thus showing increased neural cell apoptosis in patients with PD.

Cerebrospinal fluid tissue transglutaminase as a biochemical marker for Alzheimer's disease.

Tissue transglutaminase (tTG) is an indicator of acute cell death in vitro. An increase in tTG protein level is found in postmortem Alzheimer's disease (AD) brains as well as in Huntington's disease. No study revealed tTG in vivo so far. We investigated the concentrations of tTG in the cerebrospinal fluid (CSF) obtained from 84 patients using ELISA assays. We compared 33 patients with probable AD to 18 patients with probable vascular dementia (VaD) and 33 control patients without neuropsychological deficit. Diagnosis was supported by CSF parameter and neuroimaging. We found a highly significant difference (P = 0.001) between the concentration of tTG in the AD groups (7.58 pg/ml) and controls (2.99 pg/ml). There was no statistical difference between controls and VaD (2.93 pg/ml). Interestingly, tTG did not show an association with tau protein, Abeta42, apoE4, neuropsychological items, or age. Males showed lower tTG values than females; however, this difference did not reach statistical significance. To our knowledge, this is the first demonstration that tTG is increased in AD in vivo. Our results suggest that tTG may be a powerful biochemical marker of the acute degenerating process in vivo. It may serve as completion of CSF analysis in the diagnosis of dementing disorders and may be a simple way of assessing the efficacy of possible new antiapoptotic drugs.

Cerebrospinal fluid tissue transglutaminase in vascular dementia.

The enzyme tissue transglutaminase (tTG), an indicator of acute cell death, is found in brains of Alzheimer's and Huntington's disease patients. tTG, as a specific marker for apoptosis, may therefore be a powerful biochemical marker of the acute degenerating process in vivo and may be useful in discrimination between vascular dementia (VaD) and Alzheimer's disease (AD). It may serve as completion of CSF analysis in diagnosis of dementing disorders and be a simple way of assessing the efficacy of possible new anti-apoptotic drugs.

Transglutaminase activity in serum and cerebrospinal fluid in sporadic amyotrophic lateral sclerosis: a possible use as an indicator of extent of the motor neuron loss.

The activity of transglutaminase (TGase), a marker enzyme for tissue degeneration, was examined in serum and cerebrospinal fluid (CSF) obtained from patients with sporadic amyotrophic lateral sclerosis (SALS), and compared to those from patients without SALS. When the serum TGase activity values from SALS patients were compared against the 'ALS-scale', which is used for clinical evaluation of the progression of ALS, the TGase activity values were higher at the initial stage of the disease than in non-ALS subjects, whereas they became extremely low at the late stage of ALS. The TGase activity in the CSF taken at later than middle stage from ALS patients with definite clinical motor dysfunctions was significantly lower than in that from non-ALS subjects. We have previously demonstrated marked reduction of tissue TGase activity in all regions of spinal cord tissue transections from ALS patients, not only in ventral but also lateral and dorsal regions, relative to that in non-ALS patients. These results suggest that some TGase may be leaked out of the spinal cord tissue into the CSF and then into the blood-stream during the progression of ALS, and the enzymic activity finally becomes depleted at the terminal stages of the disease when most of the spinal motor neuronal perikarya have been destroyed.