Showing papers on "Aging brain published in 1998"

Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity.

Abstract: The formation of fibrillar deposits of amyloid beta protein (Abeta) in the brain is a pathological hallmark of Alzheimer's disease (AD). A central question is whether Abeta plays a direct role in the neurodegenerative process in AD. The involvement of Abeta in the neurodegenerative process is suggested by the neurotoxicity of the fibrillar form of Abeta in vitro. However, mice transgenic for the Abeta precursor protein that develop amyloid deposits in the brain do not show the degree of neuronal loss or tau phosphorylation found in AD. Here we show that microinjection of plaque-equivalent concentrations of fibrillar, but not soluble, Abeta in the aged rhesus monkey cerebral cortex results in profound neuronal loss, tau phosphorylation and microglial proliferation. Fibrillar Abeta at plaque-equivalent concentrations is not toxic in the young adult rhesus brain. Abeta toxicity in vivo is also highly species-specific; toxicity is greater in aged rhesus monkeys than in aged marmoset monkeys, and is not significant in aged rats. These results suggest that Abeta neurotoxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contribute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to Abeta neurotoxicity.

Strong nuclear factor-κB-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic alzheimer's disease superior temporal lobe neocortex

Abstract: Cyclooxygenase-2 (COX-2; EC 1.14.99.1) RNA message abundance in 25 control and Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-confirmed sporadic Alzheimer's disease (AD) brains is remarkably heterogeneous when compared with 55 other AD brain RNA message levels that were previously characterized (Lukiw and Bazan: J Neurosci Res 50:937–945, 1997). Examination of nuclear protein extracts (NPXTs) that were derived from control and AD-affected brain neocortical nuclei (n = 20; age range, 60–82 years; postmortem interval, 0.5–6.5 hours) by using gel shift, gel supershift, and cold oligonucleotide competition assay revealed a highly significant relationship between the extent of inflammatory transcription factor, nuclear factor (NF)-κB: DNA binding and the abundance of the COX-2 RNA signal (P 0.045). These data are the first linking inflammation-related transcription factor NF-κB-DNA binding to up-regulation of transcription from a key inflammatory gene, COX-2, in both normally aging brain and in AD-affected neocortex. Systematic deletion of NF-κB-DNA binding sites in human COX-2 promoter constructs attenuates COX-2 transcriptional induction by mediators of inflammation. Strong NF-κB-DNA binding has been reported previously to temporally precede COX-2 gene transcription in human epithelial (A549), hamster B-cell (HIT-T15), human endothelial (HUVEC), human lymphoblast (IM9), human fibroblast (IMR90), rat glioma/mouse neuroblastoma (NG108–15), human keratinocyte (NHEK), mouse fibroblast (NIH 3T3), rat neuroblastoma (SH-SY5Y) cell lines and in mouse and rat brain hippocampus, indicating a highly conserved inflammatory signaling pathway that is common to diverse species and cell types. The mouse, rat, and human COX-2 immediate promoters, despite 7.5 × 107 years of DNA sequence divergence, each retain multiple recognition sites specific for NF-κB-DNA binding. These data suggest that basic gene induction mechanisms, which have been conserved over long periods of evolution, that increase NF-κB-DNA binding may be fundamental in driving transcription from inflammation-related genes, such as COX-2, that operate in stressed tissues, in normally aging cell lines, and in neurodegenerative disorders that include AD brain. J. Neurosci. Res. 53:583–592, 1998. © 1998 Wiley-Liss, Inc.

Does Overexpression of βAPP in Aging Muscle Have a Pathogenic Role and a Relevance to Alzheimer’s Disease? : Clues from Inclusion Body Myositis, Cultured Human Muscle, and Transgenic Mice

Abstract: In Alzheimer’s disease (AD) pathogenesis, an underlying βAPP/Aβ dysmetabolism leading to neuronal toxicity is considered the essential abnormality by most investigators. 1-4 Hyperphosphorylation and filamentogenesis of tau into paired helical filaments (PHFs) is also thought to be important 5,6 and apolipoprotein E4 genotype is considered an aggravating factor. 7 The various hypotheses for sporadic AD (s-AD) acknowledge the milieu of aging brain cells but usually omit consideration of an initial sparking event. For several years it was presumed that βAPP/Aβ and tau abnormalities occur only in the brain (and its blood vessels in regard to βAPP/Aβ), until βAPP, Aβ, and PHFs containing hyperphosphorylated tau were shown to accumulate pathologically within abnormal muscle fibers of two closely related, progressively disabling muscle diseases, sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM). 8-10 s-IBM is a disease of aging muscle with clinical onset nearly always at age 50 or older; h-IBM begins clinically at ages 15–30 in young adult muscle. 11 The autosomal-recessive form of h-IBM is caused by a yet-undetermined gene on chromosome 9 p1-q1, 12,13 not a defect of the βAPP gene on chromosome 21; in two families with the autosomal-dominant form of h-IBM, no defect of the βAPP-gene was demonstrable. 14 s-IBM is the most common muscle disease in older patients. h-IBM is rather rare, but probably more common than hereditary AD (h-AD). In s-IBM and h-IBM it was shown that βAPP-mRNA was overexpressed in muscle fibers 15 (but not exclusively; cellular prion protein and its mRNA were also overexpressed). 16 Several other “Alzheimer characteristic” proteins, including presenilin-1 and proteins related to oxidative stress, also accumulated within abnormal muscle fibers of s-IBM and h-IBM. 11,17,18 Intracellular congophilic amyloid deposits are another characteristic and consistent feature of s-IBM muscle fibers. 8,19 In h-IBM they are very rare in younger patients, but their occurrence, especially in autosomal-dominant forms, increases in older patients. 11 The intracellular amyloid of the IBMs is of two structural-chemical types: collections of 15- to 21-nm PHFs containing immunoreactive tau (and other components, but not Aβ), and collections (“microplaquettes”) containing 6- to 10-nm filaments immunoreactive for Aβ. 11 Because the same proteins accumulate within s- and h-IBM muscle fibers as accumulate in the brains of patients with sporadic and hereditary forms of AD, the muscle and brain diseases might share certain pathogenic steps and knowledge of one disease might help elucidate the other. Cellular aging and evidence of oxidative stress are associated with the IBMs and the ADs. The IBMs and the ADs are both multifactorial and polygenetic. The respective cascades of events leading to the specific form of AD-like IBM muscle fiber degeneration and the similar specific features in AD brain are not understood. Within both the IBM and the AD categories, the pathological phenotypes of sporadic and hereditary forms are very similar, despite the different direct causes being mainly nongenetic versus mainly genetic. Therefore, in each disease category it has been proposed, by our group for the IBMs 20,21 and by others for the ADs, 22,23 that different etiologies including different genetic defects in the hereditary forms lead to the same upstream step, which then promotes the final common downstream pathogenic cascade of events resulting in the specific cellular deterioration. Moreover, the intracellular pathogenic cascades of the IBMs and the ADs might have strong similarities following determination by yet-unknown factors of the initial tissue selectivity in each category, muscle versus brain. In both s-IBM and h-IBM, it is of particular interest that individual muscle fibers accumulate N- and C-terminal βAPP and Aβ, and βAPP-mRNA, before other abnormalities are evident. 8-11 We hypothesized that overexpression of βAPP might be upstream to other cellular abnormalities, including oxidative stress and mitochondrial abnormalities (Figure 1) ▶ . 21 To test this hypothesis, wild-type full-length 751 βAPP was overexpressed long-term in cultured normal human muscle. It produced within muscle fibers several aspects of the IBM cellular phenotype, including vacuolization, congophilic amyloid inclusions (as microplaquettes) in a small percentage of muscle fibers, cytoplasmic 6- to 10-nm amyloid-like filaments, nuclear PHFs, mitochondrial cytochrome oxidase deficiency, and mitochondrial morphological abnormalities. 24,25 Figure 1. Genetic defects in h-IBM and various factors (including a putative virus) in s-IBM lead to presently unknown mechanisms [“?” box in diagram]. These up-regulate βAPP transcription, resulting in βAPP overexpression. ...

Handbook of the aging brain

Abstract: M.S. Albert, Normal and Abnormal Memory: Aging and Alzheimer's Disease. S.J. Lupien and M.J. Meaney, Stress, Glucocorticoids, and Hippocampal Aging in Rat and Human. C.A. Barnes, Spatial Cognition and Functional Alterations of Aged Rat Hippocampus. A.J. Silva, K.P. Giese, and P.W. Frankland, Identification of Molecular and Cellular Mechanisms of Learning and Memory: The Impact of Gene Targeting. B.T. Hyman and T. Gomez-Isla, Normal Aging and Alzheimer's Disease. J.-P. Julien, Transgenic Mouse Models with Neurofilament-Induced Pathologies. P.C. Wong, D.R. Borchelt, M.K. Lee, G. Thinakaran, S.S. Sisodia, and D.L. Price, Transgenic Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease. G.M. Martin, Toward a Genetic Analysis of Unusually Successful Neural Aging. R.E. Tanzi, The Role of the Presenilins in Alzheimer's Disease. J.Q. Trojanowski, J.E. Galvin, M.L. Schmidt, P.-H. Tu, T. Iwatsubo, and V.M.-Y. Lee, Mechanisms of Neuron Death in Neurodegenerative Diseases of the Elderly: Role of the Lewy Body. S.-H. Yen, P. Nacharaju, L.-W. Ko, A. Kenessey, and W.-K. Liu, Microtubule-Associated Protein Tau: Biochemical Modifications, Degradation and Alzheimer's Disease. K.S. Kosik, C. Ho, U. Liyange, C. Lemere, M. Medina, and J. Zhou, A Novel Gene in the Armadillo Family Interacts with Presenilin 1. R. Quirion, D. Auld, U. Beffert, J. Poirier, and S. Kar, Putative Links Between Some of the Key Pathological Features of the Alzheimer's Brain. A. LeBlanc, Unraveling the Controversy of Human Prion Protein Diseases. E. Wang, Translational Control, Apoptosis, and the Aging Brain. H.M. Schipper, Astrocyte Senescence and the Pathogenesis of Parkinson's Disease. Index.

Hormones and the aging brain

Abstract: There is a growing appreciation of the role of ovarian hormones as modulators of neuronal function within the central nervous system. Ovarian failure has long been known to result in reversible changes in mental function, affect, and behavior. Only recently have we begun to appreciate the potential role of these hormones, specifically estrogen, in the aging of the brain and in the expression of Alzheimer's disease. As a consequence of the estrogen deficiency state of the postmenopausal woman, brain aging may be accelerated, resulting in the greater incidence of injurious falls and accidental injuries in women than in men of the same age. This sex steroid deficiency in postmenopausal women may also account for the earlier expression of Alzheimer's disease in women.

Reactive Oxygen Involvement in Neurodegenerative Pathways

Abstract: As organs age, the likelihood of severe dysfunction increases steadily. The brain is particularly sensitive to age-related, chronic and acute oxidative pathologies. An emerging paradigm holds that diverse neurodegenerative conditions share a common etiological factor, namely, enhanced brain tissue oxidation owing to exacerbated production of reactive oxygen species (ROS) or to compromise of antioxidant defense and repair mechanisms. Brain is particularly susceptible to oxidative stress owing to its high content of unsaturated lipids, high metabolic rate, relative dearth of antioxidant enzymes, and inability to regenerate lost neurons. Pathogenic ROS generation may result from metabolic enzyme dysregulation, impaired mitochondrial respiration, excitotoxic stimulation, and secondarily as a function of intracellular calcium stress (summarized in Fig. 1 and elaborated below). Natural variation in antioxidant systems may explain why humans differ so greatly with respect to pathways and rates of neurodegeneration. If this is the case, antioxidant supplementation of the aging brain may forestall certain aspects of age-related neurodegeneration. Accordingly, much research has focused on antioxidant management of aging brain and on antioxidant interdiction of postischemic brain damage. Recent findings indicate that specific antioxidants do more than scavenge ROS, but may indirectly affect cellular signal transduction, genetic response, and inflammatory events in such a way as to modulate beneficially brain response to oxidative challenge.