Cellular responses to increased oxidative stress appear to be a mechanism that contributes to the varied cytopathology of Alzheimer's 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-a and JNK3/SAPK-b were related to neuro®brillary pathology and JNK1/SAP-Kg 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 neuro®brillar alterations including neuro®brillary tangles, senile plaque neurites, neuropil threads and granulovacuolar degeneration structures (GVD), completely overlapping with t-positive neuro®brillary 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 signi®cantly increased in AD over control cases. Together, these ®ndings suggest that JNK/SAPK dysregulation, probably resulting from oxidative stress, plays an important role in the increased phosphorylation of cytoskeletal proteins found in AD.

The temporal association between oxidative stress and the hallmark pathologies of Alzheimer disease (AD) demonstrates that oxidative stress is among the earliest events in the disease. Nonetheless, neither the consequences of oxidative stress nor how oxidative stress relates to other pathological features of the disease are clear at this point. To begin to address these issues, we investigated p38 kinase, which is induced by oxidative stress, in the pathogenesis of AD. In hippocampal and cortical brain regions of individuals with AD, p38 is exclusively localized in association with neurofibrillar pathology. By marked contrast, these brain regions exhibit a low level of diffuse p38 staining in the neuronal cytoplasm in controls. We found a complete overlap of the immunostaining profiles of p38 and tau-positive neurofibrillary pathology and that the majority of p38 was activated in AD neurons, both of which support an association of p38 with the disease process. Moreover, the finding that PHF-tau co-immunoprecipitates with p38, and that p38 co-purifies with PHF-tau, strongly suggests that they are physically associated in vivo. Since p38 is also implicated in cell cycle regulation, our findings provide a link between the cell cycle re-entrant phenotype, cytoskeletal phosphorylation and oxidative stress in AD.

Mitogen-activated protein kinase

A number of recent findings have highlighted the similarities between neurogenesis during development and neurodegeneration during Alzheimer disease. In fact, neuronal populations that are known to degenerate in Alzheimer disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. In this study, we extended these findings by investigating components of the cell cycle, known to trigger progression through G1 through activation of signal transduction cascades. Specifically, we found that proteins implicated in G1 transition, namely Cdc42/Rac, are upregulated in select neuronal populations in cases of Alzheimer disease in comparison to age-matched controls. Importantly, Cdc42/Rac shows considerable overlap with early cytoskeletal abnormalities suggesting that these changes are an extremely proximal event in the pathogenesis of the disease. Given the functional role of Cdc42/Rac in various cellular processes known to be perturbed in Alzheimer disease, namely cytoskeletal organization, oxidative balance, and oncogenic signaling, it is likely that increased neuronal Cdc42/Rac is highly significant in relation to the pathogenic process and contributes to neuronal degeneration. In fact, these findings suggest that Alzheimer disease is an oncogenic process.

Multiple studies suggest that neuronal death in Alzheimer's 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 cas-pase-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.