Characteristic analysis of Zenker's diverticulum incidentally detected on multimodal neck ultrasound.

PURPOSE: Zenker's diverticulum (ZD) incidentally detected on neck ultrasound (US) could be easily misdiagnosed as a thyroid nodule and unnecessarily removed by surgical operation. It is a critical issue to identify the characteristics of ZD in clinical practice. METHODS: We reported 10 cases of ZD diagnosed using multimodal US, and discussed the features of its multimodal US images extracted from grayscale sonograms, color Doppler flow imaging (CDFI), three-dimensional US (3D-US), and contrast-enhanced US (CEUS). RESULTS: All lesions were heterogeneous in the posterior of the left thyroid. CDFI showed no blood flow within the lesions. The shapes and internal echoes of the masses changed when patients swallowed or drank. Performing CEUS or 3D-US for those with atypical US findings was complementary to make the final diagnosis. Importantly, multimodal US helped to diagnose suspected small lesions in three cases in which the barium esophagram tests proved negative. CONCLUSIONS: The US features of ZD detected by multiple modes of US can help in the collection of comprehensive imaging information on ZD, which should be used proactively to facilitate the correct diagnosis and to avoid misdiagnosis of ZD.

Free vascularised fibular graft for post-traumatic osteonecrosis of the femoral head in teenage patients.

Free vascularised fibular grafting has been reported to be successful for adult patients with osteonecrosis of the femoral head (ONFH). However, its benefit in teenage patients with post-traumatic ONFH has not been determined. We evaluated the effectiveness of free vascularised fibular grafting in the treatment of this condition in children and adolescents. We retrospectively analysed 28 hips in 28 patients in whom an osteonecrotic femoral head had been treated with free vascularised fibular grafting between 2002 and 2008. Their mean age was 16.3 years (13 to 19). The stage of the disease at time of surgery, and results of treatment including pre- and post-operative Harris hip scores, were studied. We defined clinical failure as conversion to total hip replacement. All patients were followed up for a mean of four years (2 to 7). The mean Harris hip score improved from 60.4 (37 to 84) pre-operatively to 94.2 (87 to 100) at final follow-up. At the latest follow-up we found improved or unchanged radiographs in all four initially stage II hips and in 23 of 24 stage III or IV hips. Only one hip (stage V) deteriorated. No patient underwent total hip replacement. Free vascularised fibular grafting is indicated for the treatment of post-traumatic ONFH in teenage patients.

Curative effect and safety of vascularized fibula grafting in renal transplant recipients with osteonecrosis of the femoral head: three case reports.

Osteonecrosis of the femoral head is a common and severe complication after renal transplantation. It is characterized by deterioration of hip joint function, which impairs quality of life. We present 3 renal transplant case reports of patients with osteonecrosis of the femoral head who underwent free vascularized fibular grafting at our hospital. Follow-up was from 1(1/2) to 2 years. All 3 patients exhibited good recovery with substantial improvement in joint function. Intraoperative and postoperative findings demonstrated the safety of this surgical procedure.

Treatment of femoral head osteonecrosis in patients with systemic lupus erythematosus by free vascularised fibular grafting.

The purpose of this study was to review the radiographs of symptomatic femoral head osteonecrosis in patients with systemic lupus erythematosus (SLE) and to assess the results of treatment using free vascularised fibular grafting. We retrospectively reviewed 50 patients (80 hips) with SLE who underwent free vascularised fibular grafting for osteonecrosis of the femoral head. All patients were followed up for at least 2 or more years (average, 4.3 years). The mean Harris hip score improved from 72 to 88. At the latest follow-up, we found improved or unchanged radiographs in 12 of initially Stage II hips and in 60 of 64 Stage III or IV hips. No hips failed treatment and underwent total hip arthroplasty. The data suggest that free vascularised fibular grafting was successful in maintaining joint function and in delaying the need for joint replacement procedure.

Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation.

Activated (phosphorylated) mitogen-activated protein kinase p38 (MAPK-p38) and interleukin-1 (IL-1) have both been implicated in the hyperphosphorylation of tau, a major component of the neurofibrillary tangles in Alzheimer's disease. This, together with findings showing that IL-1 activates MAPK-p38 in vitro and is markedly overexpressed in Alzheimer brain, suggest a role for IL-1-induced MAPK-p38 activation in the genesis of neurofibrillary pathology in Alzheimer's disease. We found frequent colocalization of hyperphosphorylated tau protein (AT8 antibody) and activated MAPK-p38 in neurons and in dystrophic neurites in Alzheimer brain, and frequent association of these structures with activated microglia overexpressing IL-1. Tissue levels of IL-1 mRNA as well as of both phosphorylated and non-phosphorylated isoforms of tau were elevated in these brains. Significant correlations were found between the numbers of AT8- and MAPK-p38-immunoreactive neurons, and between the numbers of activated microglia overexpressing IL-1 and the numbers of both AT8- and MAPK-p38-immunoreactive neurons. Furthermore, rats bearing IL-1-impregnated pellets showed a six- to seven-fold increase in the levels of MAPK-p38 mRNA, compared with rats with vehicle-only pellets (P<0.0001). These results suggest that microglial activation and IL-1 overexpression are part of a feedback cascade in which MAPK-p38 overexpression and activation leads to tau hyperphosphorylation and neurofibrillary pathology in Alzheimer's disease.

Neuronal DNA damage correlates with overexpression of interleukin-1beta converting enzyme in APPV717F mice.

Transgenic APPV717F mice, homozygous for a human minigene encoding the V717F familial Alzheimer's disease mutation, develop Abeta plaques similar to those seen in Alzheimer patients and show evidence of neuronal cell drop out in CA2-3 regions of the hippocampus at 8 months of age and older. Interleukin-1 (IL-1)beta (IL-1beta) converting enzyme (ICE) is a cysteine protease (caspase-1) that processes inactive (33 kDa) pro-IL-1beta to the active (17 kDa) inflammatory cytokine. We used immunohistochemistry, RT-PCR, and DNA cleavage (TUNEL) analysis to show progressive, age-associated increases in ICE mRNA levels, in the numbers of ICE-immunoreactive glia, and in the numbers of neurons showing evidence of DNA damage in APPV717F mice that commenced months prior to the appearance of Abeta plaques. Moreover, there were significant correlations between these parameters over an age range of 1-17 months. These findings are consistent with the idea that increases in ICE activity and expression contribute to neuronal injury in Alzheimer's disease.

The pervasiveness of interleukin-1 in alzheimer pathogenesis: a role for specific polymorphisms in disease risk.

Interleukin-1 (IL-1) has been implicated as a key molecule in Alzheimer pathogenesis based on findings of an IL-1 overexpression in Alzheimer brain that is directly related to plaque progression and tangle formation, and on findings that IL-1 induces excessive synthesis, translation, and processing of neuronal beta-amyloid precursor protein (betaAPP) as well as synthesis of most known plaque-associated proteins. In addition, IL-1 activates astrocytes, with the important consequence of overexpression of the neuritogenic cytokine S100beta and overgrowth of dystrophic neurites in neuritic plaques. As further evidence of the importance of IL-1 in Alzheimer pathogenesis, two new genetic studies of inheritance of specific polymorphisms in IL-1 genes in Alzheimer and control patients show that homozygosity for a specific IL-1A gene polymorphism at least triples risk for development of Alzheimer's disease. This increase is associated with earlier age of onset. Homozygosity for this polymorphism plus another in the IL-1B gene further increases risk.

Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo.

Slow-release, IL-1-impregnated pellets implanted in rat cerebral cortex to simulate chronic overexpression of IL-1 significantly increased relative tissue levels of tau mRNA and of tau immunoreactivity in neuronal cell bodies and in swollen dystrophic neurites that also overexpressed phosphorylated and nonphosphorylated neurofilament epitopes. In addition, rats with IL-1-impregnated pellets, but not control rats or those with sham pellets, showed focal immunoreactivity for hyperphosphorylated tau epitopes present in paired helical filaments. Our results are consistent with an important driving role for IL-1 in the pathogenesis of Alzheimer-type neuronal and neuritic changes.

Overexpression of the neuritotrophic cytokine S100beta precedes the appearance of neuritic beta-amyloid plaques in APPV717F mice.

Homozygous APPV717F transgenic mice overexpress a human beta-amyloid precursor protein (betaAPP) minigene encoding a familial Alzheimer's disease mutation. These mice develop Alzheimer-type neuritic beta-amyloid plaques surrounded by astrocytes. S100beta is an astrocyte-derived cytokine that promotes neurite growth and promotes excessive expression of betaAPP. S100beta overexpression in Alzheimer's disease correlates with the proliferation of betaAPP-immunoreactive neurites in beta-amyloid plaques. We found age-related increases in tissue levels of both betaAPP and S100beta mRNA in transgenic mice. Neuronal betaAPP overexpression was found in cell somas in young mice, whereas older mice showed betaAPP overexpression in dystrophic neurites in plaques. These age-related changes were accompanied by progressive increases in S100beta expression, as determined by S100beta load (percent immunoreactive area). These increases were evident as early as 1 and 2 months of age, months before the appearance of beta-amyloid deposits in these mice. Such precocious astrocyte activation and S100beta overexpression are similar to our earlier findings in Down's syndrome. Accelerated age-related overexpression of S100beta may interact with age-associated overexpression of mutant betaAPP in transgenic mice to promote development of Alzheimer-like neuropathological changes.

Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression.

Cholinergic dysfunction in Alzheimer's disease has been attributed to stress-induced increases in acetylcholinesterase (AChE) activity. Interleukin-1 (IL-1) is overexpressed in Alzheimer's disease, and stress-related changes in long-term potentiation, an ACh-related cerebral function, are triggered by interleukin-1. Microglial cultures (N9) synthesized and released IL-1 in response to conditioned media obtained from glutamate-treated primary neuron cultures or PC12 cells. This conditioned media contained elevated levels of secreted beta-amyloid precursor protein (sAPP). Naive PC12 cells cocultured with stimulated N9 cultures showed increased AChE activity and mRNA expression. These effects on AChE expression and activity could be blocked by either preincubating the glutamate-treated PC12 supernatants with anti-sAPP antibodies or preincubating naive PC12 cells with IL-1 receptor antagonist. These findings were confirmed in vivo; IL-1-containing pellets implanted into rat cortex also increased AChE mRNA levels. Neuronal stress in Alzheimer's disease may induce increases in AChE expression and activity through a molecular cascade that is mediated by sAPP-induced microglial activation and consequent overexpression of IL-1.

Overexpression of s100beta in Down's syndrome: correlation with patient age and with beta-amyloid deposition.

S100beta is an astrocyte-derived uritotrophic' cytokine which has been implicated in the pathogenesis of Alzheimer's disease. S100beta overexpression by plaque-associated astrocytes correlates with growth of abnormal (strophic') neurites in beta-amyloid plaques, one of the major neuropathological hallmarks of Alzheimer's disease. As the characteristic neuropathological changes of Alzheimer's disease are virtually universal in middle-aged Down's syndrome patients, studies of Down's syndrome patients provide a unique opportunity to investigate the pathophysiological processes underlying the development of Alzheimer-type neuropathological changes. Computerized morphometric analysis was used to quantify astrocyte activation and astrocytic expression of S100beta, and to correlate these with beta-amyloid deposition, in a clinically well-characterized cohort of Down's syndrome subjects, aged 13-65 years. There were significant positive correlations between S100beta expression and patient age, and between S100beta expression and cerebral cortical beta-amyloid deposition. Moreover, the numbers of activated (enlarged) astrocytes overexpressing S100beta showed a significant correlation with the numeric density of beta-amyloid plaques, from the youngest to the oldest ages and within age ranges where pathology is most florid, while no such relationship was found between the numbers of small, non-activated S100beta-immunoreactive cells and numerical density of beta-amyloid plaques. These correlations, together with established functions of S100beta, are consistent with the idea that S100beta overexpression promotes beta-amyloid plaque formation and progression in Down's syndrome.

Increased interleukin-1beta converting enzyme expression and activity in Alzheimer disease.

Increased expression of interleukin-1 in Alzheimer disease (AD) has been implicated as a driving force in neurodegenerative cascades that underlie the formation of neuritic plaques and neurofibrillary tangles, the spread of these neuropathological lesions across cerebral cortical regions, and the accompanying neuronal cell injury and loss. The beta isoform of interleukin-1 is generated from an inactive, 33-kDa precursor through the action of a specific interleukin-1beta converting enzyme (ICE), also known as caspase-1. We used mesial temporal tissue (hippocampus and parahippocampal cortex) obtained postmortem from Alzheimer and control patients for determinations of endogenous tissue ICE activity and for Western immunoblot analysis of tissue ICE concentrations. ICE activity in Alzheimer tissue was elevated 50-100% (p < 0.002, or better, at incubation times of 30 min to 10 h), and ICE protein level was elevated 180% (p = 0.01). Parahippocampal cortex of Alzheimer patients showed increased numbers of neurons with in situ evidence of DNA damage. Increased DNA degradation was also evident upon electrophoresis of isolated DNA. Overexpression and increased activity of ICE may contribute to neurodegeneration in AD through generation of biologically active interleukin-1, with consequent activation of interleukin-1-driven neurodegenerative cascades.

Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for 'hypofrontality'.

An impairment of prefrontal cortical functioning in schizophrenia ('hypofrontality') has been suggested by clinical, neuroimaging, and postmortem brain tissue studies. We used Western immunoblot and Northern hybridization analyses of postmortem brain tissue obtained from 14 schizophrenic patients and 12 control patients of similar ages to measure tissue levels of synaptophysin (a structural synaptic vesicle protein) and of SNAP-25 (a 25-kDa presynaptic protein), and their encoding mRNAs, in Brodmann's area 10 of prefrontal cortex. There were significant decreases in tissue levels of both of these proteins in prefrontal cortex of schizophrenic patients relative to controls. In contrast, tissue levels for the mRNAs encoding these proteins were not decreased in schizophrenic patients. Subsequent labeling of the same Western immunoblots showed no difference in tissue levels of glial fibrillary acidic protein (GFAP) in schizophrenic and control patients. Similarly, subsequent hybridization of the same Northern hybridization membranes showed no difference in tissue levels of GFAP mRNA or of 28S rRNA in schizophrenic and control patients. These alterations in tissue levels of synaptophysin and SNAP-25 are consistent with the idea that the clinically observed 'hypofrontality' of schizophrenia arises from abnormalities of synaptic number or structural integrity in prefrontal cortex.

Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer's disease.

Activated microglia overexpressing interleukin-1 (IL-1) are prominent neuropathological features of Alzheimer's disease. We used computerized image analysis to determine the number of IL-1 alpha-immunoreactive (IL-1 alpha +) microglia in cytoarchitectonic layers of parahippocampal gyrus (Brodmann's area 28) of Alzheimer and control patients. For cortical layers I and II, the numbers of IL-1 alpha + microglia were similar in Alzheimer and control patients. For layers III-VI, the numbers of IL-1 alpha + microglia were higher than that seen in layers I-II for both Alzheimer and control patients. Moreover, for layers III-VI, the number of IL-1 alpha + microglia in Alzheimer patients was significantly greater than that in control patients (relative Alzheimer values of threefold for layer III-V and twofold for layer VI; P < 0.05 in each case). The cortical laminar distribution of IL-1 alpha + microglia in Alzheimer patients correlated with the cortical laminar distribution of beta-amyloid precursor protein-immunoreactive (beta-APP+) neuritic plaques found in Alzheimer patients (r = 0.99, P < 0.005). Moreover, the cortical laminar distribution of IL-1 alpha + microglia in control patients also correlated with the cortical laminar distribution of beta-APP+ neuritic plaques found in Alzheimer patients (r = 0.91, P < 0.05). These correlations suggest that pre-existing laminar distribution patterns of IL-1 alpha + microglia (i.e. that seen in control patients) are important in determining the observed laminar distribution of beta-APP+ neuritic plaques in Alzheimer patients. These findings provide further support for our hypothesis that IL-1 is a key driving force in neuritic plaque formation in Alzheimer's disease.

S100 beta increases levels of beta-amyloid precursor protein and its encoding mRNA in rat neuronal cultures.

S100beta has been implicated in the formation of dystrophic neurites, overexpressing beta-amyloid precursor protein (betaAPP), in the beta-amyloid plaques of Alzheimer's disease. We assessed the effects of S100beta on cell viability of, neurite outgrowth from, and betaAPP expression by neurons in primary cultures from fetal rat cortex. S100beta (1-10 ng/ml) enhanced neuronal viability (as assessed by increased mitrochondrial activity and decreased lactic acid dehydrogenase release) and promoted neurite outgrowth. Higher levels of S100beta (100 ng/ml, but not 1 microg/ml) produced qualitatively similar, but less marked, effects. S100beta also induced increased neuronal expression of the microtubule-associated protein MAP2, an effect that is consistent with trophic effects of S100beta on neurite outgrowth. S100beta (10 and 100 ng/ml) induced graded increases in neuronal expression of betaAPP and of betaAPP mRNA. These results support our previous suggestion that excessive expression of S100beta by activated, plaque-associated astrocytes in Alzheimer's disease contributes to the appearance of dystrophic neurites overexpressing betaAPP in diffuse amyloid deposits, and thus to the conversion of these deposits into the diagnostic neuritic beta-amyloid plaques.

Progressive neuronal injury associated with amyloid plaque formation in Alzheimer disease.

Neuronal injury associated with amyloid plaque progression in Alzheimer disease was examined using TUNEL combined with beta-amyloid immunolabeling. There was a progressive increase in the frequency of TUNEL-positive neurons associated with plaque types representing a hypothesized sequence of plaque evolution, from 20% of neurons not associated with plaques to 40%, 70-80%, and 100% of neurons in diffuse, neuritic, and dense-core non-neuritic plaques, respectively. The total number of neurons associated with end-stage, dense-core, non-neuritic plaques declined by 70% (per unit plaque area) compared with neuritic plaque forms. This decline, together with the fact that virtually all of those remaining were TUNEL-positive, suggests that neuronal cell damage increases as plaques evolve from diffuse to more complex forms and that eventually all plaque-associated neurons are lost. This novel demonstration of neurotoxicity associated with amyloid plaque formation and progression suggests that plaque-associated neuronal injury is a major cause of neuronal loss in Alzheimer disease.

Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain.

Microglia-mediated inflammatory responses have been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. The strong age association of Alzheimer's disease incidence suggests that events in normal aging may promote such responses. We used immunohistochemistry and computerized image analysis to determine the numbers, size, activation state, and immunoreactive intensity of interleukin-1 alpha-immunoreactive (IL-1 alpha +) microglia in mesial temporal lobe of 20 neurologically normal individuals, 2-80 years of age. We also used Northern analysis to determine tissue levels of IL-1 alpha mRNA in an additional 11 neurologically normal individuals aged 1 day to 78 years. IL-1 alpha + microglia were characterized as primed, enlarged, or phagocytic (enlarged with heterogeneous cytoplasmic contents) based on morphology. These three microglial subtypes showed significant differences in size [27 +/- 1 58 +/- 2 114 +/- 6 (mean +/- SEM) micron 2/cell, respectively, P < 0.001 for each comparison] and in immunoreactive intensity [60 +/- 1 68 +/- 2 79 +/- 2 (arbitrary units), respectively, P < 0.001 or better for each comparison]. There were significant age-associated increases in the total numbers of activated IL-1 alpha + microglia. Among microglial subtypes, there were significant increases in the numbers of enlarged (threefold) and especially phagocytic (elevenfold), but not primed, microglia. Tissue IL-1 alpha mRNA levels were higher in individuals over 60 than in those less than 60 (P < 0.05). The age-associated increases in microglial activation were independent of postmortem interval, patient sex, and the presence of Alzheimer-type 'senile' changes. Age-associated increases in microglial activation and IL-1 expression may contribute to the age-associated increased risk of Alzheimer's disease.

Progressive neuronal DNA damage associated with neurofibrillary tangle formation in Alzheimer disease.

DNA damage, as demonstrated by in situ Tdt-mediated dUTP-X-nick end labeling (TUNEL), is widespread in the cerebral cortex in end-stage Alzheimer disease, but has not been previously correlated with stages of neurofibrillary tangle formation. To assess possible relationships between neurofibrillary tangle formation and DNA damage, we used tau immunohistochemistry and TUNEL in tangle-rich fields of tissue sections of subiculum and parahippocampal cortex tissue from 12 Alzheimer and 6 control patients. Structures were classified and quantified as tau-/TUNEL-, tau-/TUNEL+, tau+/TUNEL-, or tau+/TUNEL+. Tau+ structures were subclassified into 4 stages (0-3) based on neurofibrillary tangle morphology. The total number of TUNEL+ neurons was significantly less in control than in Alzheimer patients (35 +/- 7.2 vs 90 +/- 9.3/mm2; mean +/- SEM; p < 0.05). The number of tau+/TUNEL+ neurons (40 +/- 1/mm2) was less than that of tau-/TUNEL- neurons (68 +/- 7/mm2) or tau-/TUNEL+ neurons in the same fields (50 +/- 4/mm2, p < 0.0001). Tau+/TUNEL- structures were fewer in number (21 +/- 1/mm2), with a third of these representing acellular "ghost tangles" (stage 3). Tau+ neurons were more likely than tau- neurons to be TUNEL+ (64 +/- 6% vs 44 +/- 2%; mean +/- SEM; p < 0.01), although most TUNEL+ neurons were tau-, even in these selected, tangle-rich fields. TUNEL positivity was not uniformly distributed among tangle stages. TUNEL positivity was less common among early (stage 0) tangles than in tau neurons (21 +/- 6% vs 44 +/- 2%; p < 0.001), but this rose to 53% among intermediate (stage 1) tangles, and to 87% among late (stage 2) tangles. We suggest that early stages of neurofibrillary tangle formation occur in a subpopulation of relatively healthy (TUNEL-) neurons, and that tangle progression is accompanied by increasing neuronal morbidity.

Senescence-accelerated overexpression of S100beta in brain of SAMP6 mice.

S100beta is an astrocyte-derived protein with paracrine and autocrine effects on neurons and glia. Brain S100beta expression increases progressively with age, and this increased expression has been implicated as a factor underlying the increasing risk of Alzheimer's disease that accompanies aging. Senescence acceleration-prone (SAMP) mice are a group of inbred strains that provide animal models of aging and of various age-related disease processes in the brain and peripheral tissues. One of these strains, the osteopenic SAMP6, has not been previously associated with central nervous system alterations. We used Northern and Western immunoblot analysis and immunohistochemical labeling to examine S100beta expression in brains of SAMP6 mice. Cerebral tissue levels of S100beta and of S100beta mRNA were 2.2-fold and 1.6-fold those of senescence-resistant (control) mice at 4 months of age (p < 0.05 in each case), and were 3.7-fold and 1.9-fold those of control mice at 6 months of age (p < 0.01 in each case). In contrast, levels of glial fibrillary acidic protein (GFAP) in cerebral hemispheres were not different from those of controls. Image analysis of immunohistochemical preparations showed increased numbers and immunoreactive intensity of S100beta-immunoreactive astrocytes in both the hippocampus and cerebral cortex of SAMP6 mice at 4 months of age (p < 0.05 or better in each case). These increases were greater in the hippocampus than in the cerebral cortex. In contrast, increases in numbers of GFAP immunoreactive astrocytes were noted only in the hippocampus. Our finding of increased S100beta gene expression in brains of SAMP6 mice mirror age-associated increases in S100beta expression in human brain and suggest that SAMP6 may provide insights into age-associated brain alterations and diseases.

Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression.

The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the beta-amyloid precursor protein, thus favoring continuing deposition of beta-amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100beta, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.