The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.
Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein.Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.
Neurofibrillary tangles (NFTs) are found in a wide range of neurodegenerative disorders, including Alzheimer's disease. The major component of NFTs is aberrantly hyperphosphorylated microtubule-associated protein tau. Because appropriate in vivo models have been lacking, the role of tau phosphorylation in NFTs formation has remained elusive. Here, we describe a new model in which adenovirus-mediated gene expression of tau, ⌬MEKK, JNK3, and GSK-3 in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100. Furthermore, this coexpression resulted in the formation of tau aggregates having short fibrils that were detergent-insoluble and Thioflavin-S-reactive. These results suggest that aberrant tau phosphorylation by the combination of these kinases may be involved in "pretangle," oligomeric tau fibril formation in vivo.Filamentous tau aggregates is the major component of neurofibrillary tangles (NFTs) 1 (1), the most common neuropathological hallmark in several neurodegenerative disorders, including Alzheimer's disease (AD). Discovery of the molecular mechanisms of NFT formation may provide more direct insight into the process of neurodegeneration in AD. NFTs consist of highly phosphorylated microtubule-associated protein tau that assembles to form fibrils with -sheet structures within the cell body and dendrites of neurons (2, 3). Several in vitro studies reveal that the repeat domain of tau aggregates more readily than full-length tau (4, 5) and forms the core of tau fibrils in AD (6). Moreover, this aggregate formation is enhanced by the existence of a polyanion such as heparin (7,8) or by RNA (9) or fatty acids (10) in the absence of tau phosphorylation. However, these in vitro conditions may not be relevant to the mechanism underlying the formation of NFTs, because tau is always aberrantly hyperphosphorylated in AD. Therefore, it would seem necessary to consider the role of hyperphosphorylation of tau in the abnormal aggregation of filamentous tau.The assembly of phosphorylated tau was also observed during the presence of 4-hydoroxy-2-nonenal (11), a lipid peroxidation by-product of oxidative stress. Increased oxidative stress is reported to occur in AD (12-15). Interestingly, phospho-tau immunoreactive neurons are also stained positively with 8-hydroxy-oxyguanine, another marker for oxidative stress (16, 17). These results suggest that oxidative stress may, in part, trigger the formation of NFTs. If oxidative stress does participate in NFTs formation in AD, such stress can lead to the activation of kinases that phosphorylate tau and stimulate NFT formation. One such candidate kinase is stress-activated protein kinase/ c-Jun N-terminal kinase (SAPK/JNK), a member of the mitogen-activated protein kinase family that is activated by several kinase cascades. Recent studies, employing antibodies against paired helical filaments (PHFs), have reported that activated phospho-JNK co-localized in neurons displaying PHF immunoreactivities (18,19). Phospho-JNK was also shown to trans...
We reviewed Alzheimer's cases with spastic paresis and cotton wool type plaques in five Japanese and nine Caucasian cases. Most were early onset familial Alzheimer's disease with presenilin 1 mutations. The cotton wool type plaques were related to extremely high production of A42, due mainly to presenilin 1 mutations and low immune responses. Cotton wool plaques were numerous in the entire central nervous system, including basal ganglia, brainstem and even in spinal cord. Cotton wool type plaques were composed of slightly electron dense synaptic structures, but amyloid fibrils were rarely found. Such a high accumulation of A42 may cause degeneration of the pyramidal tract and basal ganglia from an early stage of Alzheimer's disease.
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