Peripheral Levels of AGEs and Astrocyte Alterations in the Hippocampus of STZ-Diabetic Rats.

Diabetic patients and streptozotocin (STZ)-induced diabetes mellitus (DM) models exhibit signals of brain dysfunction, evidenced by neuronal damage and memory impairment. Astrocytes surrounding capillaries and synapses modulate many brain activities that are connected to neuronal function, such as nutrient flux and glutamatergic neurotransmission. As such, cognitive changes observed in diabetic patients and experimental models could be related to astroglial alterations. Herein, we investigate specific astrocyte changes in the rat hippocampus in a model of DM induced by STZ, particularly looking at glial fibrillary acidic protein (GFAP), S100B protein and glutamate uptake, as well as the content of advanced glycated end products (AGEs) in serum and cerebrospinal fluid (CSF), as a consequence of elevated hyperglycemia and the content of receptor for AGEs in the hippocampus. We found clear peripheral alterations, including hyperglycemia, low levels of proinsulin C-peptide, elevated levels of AGEs in serum and CSF, as well as an increase in RAGE in hippocampal tissue. We found specific astroglial abnormalities in this brain region, such as reduced S100B content, reduced glutamate uptake and increased S100B secretion, which were not accompanied by changes in GFAP. We also observed an increase in the glucose transporter, GLUT-1. All these changes may result from RAGE-induced inflammation; these astroglial alterations together with the reduced content of GluN1, a subunit of the NMDA receptor, in the hippocampus may be associated with the impairment of glutamatergic communication in diabetic rats. These findings contribute to understanding the cognitive deficits in diabetic patients and experimental models.

Diagnostic utility of serum or cerebrospinal fluid levels of toxic advanced glycation end-products (TAGE) in early detection of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques and neurofibrillary tangles (NFTs), the major constituents of which are amyloid beta protein (A beta) and tau protein, respectively. Based on the disease pathology, numerous blood and cerebrospinal fluid (CSF) tests have been proposed for early detection of AD. However, there is no definite clinical method to determine in which patients with mild cognitive impairment will progress to AD with dementia. Therefore, to develop a novel promising biomarker for early diagnosis of AD is urgently needed. Several epidemiological studies have reported moderately increased risks for AD in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end-products (AGEs), senescent macroprotein derivatives, progress more rapidly. In addition, recent understanding of this process has confirmed that AGEs-their receptor (RAGE) interactions may play a role in the pathogenesis of neurodegenerative disorders including AD. In human AD brains, AGEs are distributed in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. In this paper, we discuss the pathophysiological role for toxic AGEs (TAGE) in AD. We further review here the possibility that serum or cerebrospinal fluid levels of TAGE could become a promising biomarker for early detection of AD.

Serum or cerebrospinal fluid levels of glyceraldehyde-derived advanced glycation end products (AGEs) may be a promising biomarker for early detection of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques and neurofibrillary tangles (NFTs), the major constituents of which are the amyloid beta protein (Abeta) and tau protein, respectively. Several epidemiological studies have reported moderately increased risks of AD in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. Recent understandings of this process have confirmed that AGEs - their receptor (RAGE) interactions may play a role in the pathogenesis of diabetic vascular complications and neurodegenerative disorders including AD. Indeed, it has been demonstrated that AGEs can be identified immunohistochemically to be present in both senile plaques and NFTs from patients with AD. Glycation of Abeta markedly enhances its aggregation in vitro, and the glycation of tau, in addition to hyperphosphorylation, appears to enhance the formation of paired helical filaments. Further, RAGE has been found a specific cell surface receptor for Abeta peptite, thus eliciting neuronal cell perturbation. The active participation of RAGE in the pathogenesis of AD has also been confirmed in RAGE-overexpressed transgenic mice. Moreover, we have recently found that glyceraldehyde-derived AGEs, one of the representative ligands for RAGE, exerted cytopathic effects on cultured neuronal cells and that neurotoxic effect of diabetic serum was completely blocked by neutralizing antibodies against glyceraldehydes-derived AGEs. These observations led us to hypothesize that serum or cerebrospinal fluid (CSF) levels of glyceraldehyde-derived AGEs could become a promising biomarker for early detection of AD. We also would like to propose the possible ways of testing our hypothesis. Are the concentrations of glyceraldehyde-derived AGEs in serum or CSF elevated early in the course of dementia? Are these levels correlated with disease severity and progression, especially in patients with diabetes? These clinical studies clarify whether use of serum or CSF levels of glyceraldehyde-derived AGEs as a biomarker for AD might enable more effective diagnosis and treatment of patients with this devastating disorder.

The advanced glycation end-product N epsilon-(carboxymethyl)lysine level is elevated in cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Oxidative stress is involved in the aetiopathogenesis of amyotrophic lateral sclerosis (ALS), a fatal degenerative disorder. To test whether oxidative stress in ALS is increased and confined to the central nervous system, we have measured the glycoxidation product N(epsilon)-(carboxymethyl)lysine (CML) in serum and cerebrospinal fluid (CSF) samples by means of a novel enzyme immunoassay. Significant increases of CSF/serum ratio of CML in ALS patients (n = 25) as compared to normal controls (n = 20, p = 0.001) and to Alzheimer disease patients (n = 9, p = 0.029) suggest intrathecal production of this glycoxidation product. Measurement of CML levels may provide a novel diagnostic tool and may supplement current monitoring strategies in interventional trials.

Increased protein glycation in cerebrospinal fluid of Alzheimer's disease.

Accumulation of advanced glycation end products occurs in the brain with ageing and was proposed to be involved in pathogenesis of Alzheimer's disease. We studied changes in the level of an early glycation product, an Amadori product, in cerebrospinal fluid (CSF) in ageing and in late-onset Alzheimer's disease. The work was carried out on 99 consecutive patients. The concentration of Amadori product in CSF correlated with CSF glucose concentration but was not changed with age (n = 70). In contrast, level of CSF Amadori product was 1.7-fold higher in Alzheimer's disease patients (n = 29) as compared with non-demented age-matched control group (n = 20; P < 0.0005), although CSF glucose concentration was similar in both groups (4.1 +/- 1.3 vs. 3.8 +/- 0.6 mmol/liter, resp.). An increased accumulation of Amadori products was found in all major proteins of CSF of Alzheimer's disease including albumin, apolipoprotein E and transthyretin. We propose that the increased early glycation of CSF proteins in the Alzheimer's patients may stimulate the formation and the consequent deposition of advanced glycation end products as well as oxidative stress in the brain.