Investigations on oxidative stress and therapeutical implications in dementia

Alzheimer's disease (AD) isa progressive dementia affecting a large proport ion of the aging population. The histopathological changes in AD include ne uronal cell death and formation of amyloid plaques and neurofibrillary tang les (NFTs) NFTs are composed of hyperphosphorylated tau protein, and senile plaques contain aggregates of the beta-peptide. There is also evidence tha t brain tissue in patients with AD is exposed to oxidative stress during th e course of the disease; Advanced glycation endproducts (AGEs), which are f ormed by a nonenzymatic reaction of glucose with long-lived protein deposit s, are potentially toxic to the cell, are present in brain plaques in AD, a nd its extracellular accumulation in AD may be caused by an accelerated oxi dation of glycated proteins. The microtubuli-associated protein tau is also subject to intracellular AGE formation. AGEs participate in neuronal death causing direct (chemical) radical production: Glycated proteins produce ne arly 50-fold more radicals than non-glycated proteins, and indirect (cellul ar) radical production: Interaction of AGEs with cells increases oxidative stress. During aging cellular defence mechanisms weaken and the damages to cell constituents accumulate leading to loss of function and finally cell d eath. The development of drugs for the treatment of AD remains at a very un satisfying state. However, pharmacological approaches which break the vicio us cycles of oxidative stress and neurodegeneration offer new opportunities for the treatment of AD. Theses approaches include AGE-inhibitors, antioxi dants, and anti-inflammatory sub stances, which prevent radical production. AGE inhibitors might be able to stop formation of AGE-modified P-amyloid d eposits, antioxidants are likely to scavenge intracellular and extracellula r superoxide radicals and hydrogen peroxide before these radicals damage ce ll constituents or activate microglia, and anti-inflammatory drugs attenuat ing microglial radical and cytokine production.