Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress.

Abstract

The stability of proteins that constitute the neurofibrillary tangles and senile plaques of Alzheimer disease suggests that they would be ideal substrates for nonenzymatic glycation, a process that occurs over long times, even at normal levels of glucose, ultimately resulting in the formation of advanced glycation end products (AGEs). AGE-modified proteins aggregate, and they generate reactive oxygen intermediates. Using monospecific antibody to AGEs, we have colocalized these AGEs with paired helical filament tau in neurofibrillary tangles in sporadic Alzheimer disease. Such neurons also exhibited evidence of oxidant stress: induction of malondialdehyde epitopes and heme oxygenase 1 antigen. AGErecombinant tau generated reactive oxygen intermediates and, when introduced into the cytoplasm of SH-SY5Y neuroblastoma cells, induced oxidant stress. We propose that in Alzheimer disease, AGEs in paired helical filament tau can induce oxidant stress, thereby promoting neuronal dysfunction.Proteins or lipids exposed to reducing sugars undergo nonenzymatic glycation and oxidation, initially with formation of Schiff bases and Amadori products on free amino groups, which ultimately undergo molecular rearrangement, to form irreversible advanced glycation end products (AGEs; refs. [1][2][3][4][5]. The AGEs are heterogeneous compounds of yellowbrown color and characteristic fluorescence (1-5). Accumulation of AGEs occurs on both intra-and extracellular structures, especially those whose turnover is prolonged. Although the formation of AGEs is accelerated in diabetes, it also occurs in normal aging. Proteins with many free amino groups (i.e., with high lysine content) are most readily glycated. AGE-modified proteins form crosslinks which result in aggregation and insolubility; they are also a continuing source ofpotentially damaging reactive oxygen intermediates (ROIs) and, when present extracellularly, interact with a distinct class of receptors (1-9). In cells, we have found that AGEs impart an oxidant stress manifested in endothelium by induction of heme oxygenase, activation of the transcription factor NF-KB, and formation of malondialdehyde epitopes of lipid peroxidation products (9). These perturbations, which result in changes in a spectrum of cellular properties (e.g., cell adherence, proliferation), were not accompanied by diminished cell viability (in short-term experiments), in keeping with a role for low levels of ROIs in signal transduction.The longstanding protein aggregates in Alzheimer disease (AD), such as paired helical filament (PHF) tau and amyloid .3protein (10)(11)(12) METHODS AGE ELISA, Immunoblotting, and Immunohistohemistry. AGE antigen was determined by using affinity-purified antibody to AGEs (9,13). This antibody selectively recognizes AGE forms of multiple proteins, but not the nonglycated counterparts (9) or formylated, maleylated, oxidized, or acetylated protein (9). To assay for AGE antigen (9), an ELISA was established by coating plates with brain homogenates/PHF tau (10-100 gg/ml) ove...

Neuronal expression of myeloperoxidase is increased in Alzheimer's disease

“…Similarly, oxidative modification of tau protein can increase in vitro assembly into paired helical filaments (Schweers et al 1995;Gamblin et al 2000). Increased levels of several oxidation products have been found in AD brain including protein carbonyls (Smith et al 1998), o,o¢-dityrosine (Hensley et al 1998), AGEs (Vitek et al 1994;Yan et al 1994), 3-nitrotyrosine , lipid oxidation products Pratico et al 1998), and oxidized DNA (Mecocci et al 1994;Gabbita et al 1998). It is noteworthy that myeloperoxidase is capable of generating all of these products (Heinecke 1999;Henderson et al 2003) and that the localization of myeloperoxidase in the AD brain is similar to the localization of oxidative stress markers reported in the diseased brain: amyloid plaques (Smith et al 1994;Vitek et al 1994;Wong et al 2001), neurofilbrillary tangles (Good et al 1996;Sayre et al 1997;Smith et al 1997), and neuronal cytoplasm Smith et al 1997Smith et al , 1998.…”

“…Myeloperoxidase also oxidizes nitrite to reactive nitrogen species (Eiserich et al 1998;Byun et al 1999) and converts tyrosine to tyrosyl radical, a reactive intermediate that promotes o,o¢-dityrosine formation and initiates lipid peroxidation (Heinecke et al 1993;Savenkova et al 1994). This array of oxidatively modified amino acids bears a striking similarity to the markers of oxidative stress that are elevated in the brains of AD patients (Vitek et al 1994;Yan et al 1994;Sayre et al 1997;Hensley et al 1998;Pratico et al 1998).…”

“…Several markers of oxidative stress are increased in brain tissue from Alzheimer's patients, including advanced glycation end products (AGEs; Vitek et al 1994;Yan et al 1994), o,o¢-dityrosine (Hensley et al 1998), lipid oxidation products Pratico et al 1998), protein carbonyls (Smith et al 1998), oxidized DNA (Mecocci et al 1994;Gabbita et al 1998), and 3-nitrotyrosine . Oxidative damage occurs early in the neurodegenerative process (Nunomura et al 2001) and co-localization of oxidative stress markers with both neurofibrillary tangles (Good et al 1996;Sayre et al 1997;Smith et al 1997) and amyloid plaques (Smith et al 1994;Vitek et al 1994;Wong et al 2001;McLellan et al 2003) supports a role of oxidants in disease progression.…”

Diabetes mellitus en pacientes con enfermedad de Alzheimer: descripción clínica y correlación con el genotipo APOE en una muestra de población del departamento de Antioquia, Colombia

“…It is now considered that the AGEs play an important role in the pathophysiology of various neurological diseases via several mechanisms: (1) by modifying extracellular structural proteins; (2) by triggering intracellular processes that bind to extracellular receptors activating signal cascades; and (3) by modifying intracellular proteins. In diabetic patients, the accumulation of AGEs leads to endothelial dysfunction among other important structural changes (41)(42)(43).…”

Aluminium, β‐amyloid and non‐enzymatic glycosylation

“…Recent research has implicated the process of non-enymatic glycosylation in the aetiology of Alzheimer's disease (AD) [1,2,3]. The research has generated considerable discussion in the scientific literature [4,5] as to the role this process might play in the formation of neurofibrillary tangles and senile plaques, the characteristic pathological structures associated with AD.…”