Oxidative Stress and its Implications for Future Treatments and Management of Alzheimer Disease.

Oxidative imbalance is one of the earliest manifestations of Alzheimer disease (AD) actually preceding the classic pathology of amyloid ß deposits and neurofibrillary tangles. Clinical trials examining antioxidant modulation by a number of global interventions show efficacy, while simple supplementation has limited benefit suggesting complexity of multiple contributing factors. In this review, we highlight new insights regarding novel approaches to understanding and treating AD based on holistic views of oxidative balance including diet.

Treatment advances in Alzheimer's disease based on the oxidative stress model.

Effective therapy for Alzheimer's disease (AD), up to this point, has been hampered by our inability to diagnose the disease in its early stages, before the occurrence of significant neurodegeneration and clinical symptoms. Because AD historically has been defined by neuropathologic criteria, treatment strategies have been aimed at diminishing the pathologic end result of the disease process, namely neurodegenerative changes associated with extracellular amyloid-beta-containing plaques, as well as intracellular neurofibrillary tangles of the hyper-phosphorylated microtubule protein, tau. While these avenues continue to be pursued, results thus far have been disappointing. It is now understood that oxidative stress plays a key role in the shared pathophysiology of neurodegenerative diseases and aging. For experimental treatment of AD, the focus of research and development efforts is increasingly shifting to target mechanisms of oxidative stress. Most recently, dimebon, whose mechanism of action relates to improved mitochondrial function, has emerged as a promising candidate for experimental treatment of AD.

Iron: A Pathological Mediator of Alzheimer Disease?

Metal-catalyzed oxidation and free radical formation are potent mediators of cellular injury to every category of macromolecule found in vulnerable neuronal populations and are thought to play an early and central role in Alzheimer disease (AD) pathogenesis. While metal-binding sites are present in proteins that accumulate in AD, metal-associated redox activity is primarily noted with nucleic acids, specifically with cytoplasmic RNA. Iron dyshomeostasis in AD is thought to arise from haem breakdown and mitochondrial turnover, and a reduction in microtubule density in vulnerable neurons increases redox-active metals, initiating a cascade of events culminating in characteristic pathologic features. Increased understanding of these early changes may be translated into more effective therapeutic modalities for AD than those currently in use.

Evidence for the novel expression of human kallikrein-related peptidase 3, prostate-specific antigen, in the brain.

Human kallikrein-related peptidase 3 (hK3), also known as prostate-specific antigen (PSA), is a 33 kDa single chain glycoprotein belonging to the kallikrein family of serine proteases. With chymotrypsin-like enzymatic activity, hK3 is directly and indirectly involved in a number of diverse biological functions including male fertility, the regulation of cell proliferation, and the inhibition of angiogenesis. The gene encoding hK3, hKLK3, is located on chromosome 19 and its expression has been shown to be regulated by steroid hormones through androgen receptor-mediated transcription. hK3 was once thought to be exclusively expressed and secreted by prostatic epithelial cells, hence the initial name of prostate-specific antigen, but has since been isolated in several nonprostatic tissues and ongoing characterization of alternative splicing variants has found at least 13 distinct mRNA transcripts. The detection of hK3 in cerebrospinal fluid prompted the hypothesis that hK3 may be produced in the brain. To test this notion, in this study we used RT-PCR amplification of brain tissue total RNA and examined hK3 protein by immunohistochemical, and immunoblot analysis. RT-PCR revealed several hK3 mRNA transcripts in the brain. Confirming these findings, both immunohistochemical staining and western immunoblotting showed evidence for hK3 protein in neuronal cells. Taken together, our findings support the expression of hK3 in neuronal cells reinforcing the concept of hK3 as a ubiquitous protein with more multifarious biological activity than previously believed. Ongoing research seeks to elucidate the functional significance of hK3 in brain cells.

Menopause, estrogen, and gonadotropins in Alzheimer's disease.

For decades, Alzheimer's disease (AD) has been linked to aging, gender, and menopause. Not surprisingly, this led most investigators to focus on the role of estrogen. While undoubtedly important, estrogen is unlikely the key determinant of disease pathogenesis. Rather, it appears that estrogen may work in conjunction with a novel determinant of disease pathogenesis, namely gonadotropins. The fact that gonadotropins, specifically luteinizing hormone, play a pivotal role in disease is apparent from significant etiological, epidemiological, and pathological evidences. Moreover, targeting gonadotropins appears to have beneficial actions as a therapeutic regimen.

Sublethal RNA oxidation as a mechanism for neurodegenerative disease.

Although cellular RNA is subjected to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigations of the biological consequences of free radical damage. In fact, because it is largely single-stranded and its bases lack the protection of hydrogen bonding and binding by specific proteins, RNA may be more susceptible to oxidative insults than is DNA. Oxidative damage to protein-coding RNA or non-coding RNA will, in turn, potentially cause errors in proteins and/or dysregulation of gene expression. While less lethal than mutations in the genome, such sublethal insults to cells might be associated with underlying mechanisms of several chronic diseases, including neurodegenerative disease. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage can be demonstrated in vulnerable neurons early in disease, suggesting that RNA oxidation may actively contribute to the onset of the disease. An increasing body of evidence suggests that, mechanistically speaking, the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of protective mechanisms that prevent the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative and other degenerative diseases and lead to better therapeutic strategies.

Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance.

Accumulating evidence suggests that oxidative stress may be a major etiologic factor in initiating and promoting neurodegeneration in Alzheimer disease. Contributing to this, there is a dyshomeostasis of metal ions in Alzheimer disease with abnormally high levels of redox-active metals, particularly iron, in affected areas of the brain. Although it is unclear whether metal excesses are the sole cause of oxidative stress and neurodegeneration or a by-product of neuronal loss, the finding that metal chelators can partially solubilize amyloid-beta deposits in Alzheimer disease suggests a promising therapeutic role for chelating agents. However, the blood-brain barrier and toxicity of known chelators limit their utility. In this study, we suggest that covalent conjugation of iron chelators with nanoparticles may help overcome the limitations in blood-brain barrier permeability of existing chelation therapy. Using in vitro studies, we have shown that a chelator-nanoparticle system and the chelator-nanoparticle system complexed with iron, when incubated with human plasma, preferentially adsorb apolipoprotein E and apolipoprotein A-I, that would facilitate transport into and out of the brain via mechanisms used for transporting low-density lipoprotein. Our studies suggest a unique approach, utilizing nanoparticles, to transport chelators and chelator-metal complexes in both directions across the blood-brain barrier, thus providing safer and more effective chelation treatment in Alzheimer disease and other neurodegenerative diseases.