Arun K. Raina

Oxidative stress in Alzheimer’s disease

Oxidative balance is emerging as an important issue in understanding the pathogenesis of Alzheimers disease. Examination of Alzheimers disease brain has demonstrated a great deal of oxidative damage, associated with both hallmark pathologies (senile plaques and neurofibrillary tangles) as well as in normal appearing pyramidal neurons. While this suggests that oxidative stress is a proximal event in Alzheimers disease pathogenesis, the mechanisms by which redox balance is altered in the disease remains elusive. Determining which of the proposed sources of free radicals, which include mitochondrial dysfunction, amyloid-beta-mediated processes, transition metal accumulation and genetic factors like apolipoprotein E and presenilins, is responsible for redox imbalance will lead to a better understanding of Alzheimers disease pathogenesis and novel therapeutic approaches.

Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease.

Cellular responses to increased oxidative stress appear to be a mechanism that contributes to the varied cytopathology of Alzheimers disease (AD). In this regard, we suspect that c‐Jun N‐terminal kinase/Stress activated protein kinase (JNK/SAPK), a major cellular stress response protein induced by oxidative stress, plays an important role in Alzheimer disease in susceptible neurons facing the dilemma of proliferation or death. We found that JNK2/SAPK‐α and JNK3/SAPK‐β were related to neurofibrillary pathology and JNK1/SAP‐Kγ related to Hirano bodies in cases of AD but were only weakly diffuse in the cytoplasm in all neurons in control cases and in non‐involved neurons in diseased brain. In this regard, in hippocampal and cortical regions of individuals with severe AD, the activated phospho‐JNK/SAPK was localized exclusively in association with neurofibrillar alterations including neurofibrillary tangles, senile plaque neurites, neuropil threads and granulovacuolar degeneration structures (GVD), completely overlapping with τ‐positive neurofibrillary pathology, but was virtually absent in these brain regions in younger and age‐matched controls without pathology. However, in control patients with some pathology, as well as in mild AD cases, there was nuclear phospho‐JNK/SAPK and translocation of phospho‐JNK/SAPK from nuclei to cytoplasm, respectively, indicating that the activation and re‐distribution of JNK/SAPK correlates with the progress of the disease. By immunoblot analysis, phospho‐JNK/SAPK is significantly increased in AD over control cases. Together, these findings suggest that JNK/SAPK dysregulation, probably resulting from oxidative stress, plays an important role in the increased phosphorylation of cytoskeletal proteins found in AD.

Oxidative stress signalling in Alzheimer's disease

Multiple lines of evidence demonstrate that oxidative stress is an early event in Alzheimers disease (AD), occurring prior to cytopathology, and therefore may play a key pathogenic role in the disease. Indeed, that oxidative mechanisms are involved in the cell loss and other neuropathology associated with AD is evidenced by the large number of metabolic signs of oxidative stress as well as by markers of oxidative damage. However, what is intriguing is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated, decrease as the disease progresses to advanced AD. This finding, along with the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in AD, indicates that reactive oxygen species (ROS) not only cause damage to cellular structures but also provoke cellular responses. Mammalian cells respond to extracellular stimuli by transmitting intracellular instructions by signal transduction cascades to coordinate appropriate responses. Therefore, not surprisingly stress-activated protein kinase (SAPK) pathways, pathways that are activated by oxidative stress, are extensively activated during AD. In this paper, we review the evidence of oxidative stress and compensatory responses that occur in AD with a particular focus on the roles and mechanism of activation of SAPK pathways.

Redox-active iron mediates amyloid-β toxicity

Abstract While amyloid-β toxicity is mediated by oxidative stress and can be attenuated by antioxidants, the actual biochemical mechanism underlying neurotoxicity remains to be established. However, since aggregated amyloid-β can interact with transition metals, such as iron, both in vitro and in vivo, we suspected that bound iron might be the mediator of toxicity such that holo- and apo-amyloid would have differential effects on cellular viability. Here we demonstrate that when amyloid-β is pretreated with the iron chelator deferoxamine, neuronal toxicity is significantly attenuated while conversely, incubation of holo-amyloid-β with excess free iron restores toxicity to original levels. These data, taken together with the known sequelae of amyloid-β, suggest that the toxicity of amyloid-β is mediated, at least in part, via redox-active iron that precipitates lipid peroxidation and cellular oxidative stress.

The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease

Given the critical role of mitogen-activated protein kinase (MAPK) pathways in regulating cellular processes that are affected in Alzheimer’s disease (AD), the importance of MAPKs in disease pathogenesis is being increasingly recognized. All MAPK pathways, i.e., the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 pathways, are activated in vulnerable neurons in patients with AD suggesting that MAPK pathways are involved in the pathophysiology and pathogenesis of AD. Here we review recent findings implicating the MAPK pathways in AD and discuss the relationship between these pathways and the prominent pathological processes, i.e., tau phosphorylation and amyloid-β deposition, as well as the functional association to amyloid β protein precursor. We suggest that regulation of these pathways may be a central facet to any potential treatment for the disease.

Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation

Responses to increased oxidative stress may be the common mechanism responsible for the varied cytopathology of Alzheimer disease (AD). A possible link in support of this hypothesis is that one of the most striking features of AD, the abnormal accumulation of highly phosphorylated tau and neurofilament proteins, may be brought about by extracellular receptor kinase (ERK) whose activation is a common response to oxidative stress. In this study, we demonstrate that activated ERK is specifically increased in the same vulnerable neurons in AD that are the site of oxidative damage and abnormal phosphorylation. These findings suggest that ERK dysregulation, likley resulting from oxidative stress, could play an important role in the increased phosphorylation of cytoskeletal proteins observed in AD.

Microtubule Reduction in Alzheimer's Disease and Aging Is Independent of τ Filament Formation

Biochemical studies show that phosphorylated tau, like that found in paired helical filaments (PHFs), does not promote microtubule assembly leading to the view that PHF formation leads to microtubule deficiency in Alzheimers disease (AD). However, although this issue is one of the most important aspects to further understanding the cell biology of AD, no quantitative examination of microtubule diminution in AD and its relationship with PHFs has been performed. To examine this issue directly, we undertook a morphometric study of brain biopsy specimens from AD and control cases. Ultrastructural analysis of neurons was performed to compare the microtubule assembly state in neurons of diseased and control cases and to examine the effect of PHF accumulation. We found that both number and total length of microtubules were significantly and selectively reduced in pyramidal neurons from AD in comparison to control cases (P = 0.000004) but that this decrement in microtubule density was surprisingly unrelated to PHFs (P = 0.8). Further, we found a significant age-dependent decrease in microtubule density with aging in the control cases (P = 0.016). These findings suggest that reduction in microtubule assembly is not dependent on tau abnormalities of AD and aging.

Cyclin' toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease.

Recent evidence has associated the aberrant, proximal re‐expression of various cell cycle control elements with neuronal vulnerability in Alzheimer disease, a chronic neurodegeneration. Such ectopic localization of various cyclins, cyclin‐dependent kinases, and cyclin inhibitors in neurons can be seen as an attempt to re‐enter the cell cycle. Given that primary neurons are terminally differentiated, any attempted re‐entry into the cell division cycle in this postmitotic environment will be dysregulated. Since successful dysregulation of the cell cycle is also the hallmark of a neoplasm, early cell‐cycle pathophysiology in Alzheimer disease may recruit oncogenic signal transduction mechanisms and, hence, can be viewed as an abortive neoplastic transformation. J. Neurosci. Res. 61:128–133, 2000.

Abortive apoptosis in Alzheimer's disease

Abstract. Multiple studies suggest that neuronal death in Alzheimers disease (AD) is the result of an apoptotic mechanism. However, the stereotypical manifestations that define the terminal phases of apoptosis, such as chromatin condensation, apoptotic bodies, and blebbing, are not seen in AD. In this study, we show that the caspases, such as caspase 6, which cleave amyloid-β protein precursor (AβPP) and presenilins, are localized to the pathological lesions associated with AD. However, while upstream caspases such as 8 and 9 are clearly found in association with the intraneuronal pathology in AD, downstream caspases such as 3, 6 and 7 are present only at control levels. Given that execution of apoptosis requires amplification of the caspase-mediated apoptotic signal, our results indicate that in AD there is a lack of effective apoptotic signal propagation to downstream caspase effectors. Therefore, while the presence of caspases, especially caspase 6, in association with extracellular deposits of amyloid-β, could obviously have important ramifications on the proteolytic processing of AβPP and, thereby, on disease pathogenesis, it seems that AD represents the first in vivo situation reported in which the initiation of apoptosis does not proceed to caspase-dependent cell death. This novel phenomenon of apoptotic avoidance, which we term abortive apoptosis, or abortosis, may represent an exit from the caspase-induced apoptotic program that leads to neuronal survival in AD.

Ectopic localization of phosphorylated histone H3 in Alzheimer's disease: A mitotic catastrophe?

Despite their terminally differentiated status, vulnerable neurons in Alzheimers disease (AD) display evidence of cell cycle activation, suggesting that mitotic dysfunction may be important in disease pathogenesis. To further delineate the role of mitotic processes in disease pathogenesis, we investigated phosphorylated histone H3, a key component involved in chromosome compaction during cell division. Consistent with an activation of the mitotic machinery, we found an increase in phosphorylated histone H3 in hippocampal neurons in AD. However, rather than within the nucleus as in actively dividing cells, activated phosphorylated histone H3 in AD is restricted to the neuronal cytoplasm despite activation of the mitotic machinery. Therefore, the aberrant cytoplasmic localization of phosphorylated histone H3 indicates a mitotic catastrophe that leads to neuronal dysfunction and neurodegeneration in AD.