Age-dependent decline in density of human nerve and spinal ganglia neurons expressing the α3 isoform of Na/K-ATPase.

Ambulatory instability and falls are a major source of morbidity in the elderly. Age-related loss of tendon reflexes is a major contributing factor to this morbidity, and deterioration of the afferent limb of the stretch reflex is a potential contributing factor to such age-dependent loss of tendon reflexes. To evaluate this, we assessed the number and distribution of muscle spindle afferent fibers in human sacral spinal ganglia (S1) and tibial nerve samples obtained at autopsy, using immunohistochemical staining for the α3 isoform of Na(+), K(+)-ATPase (α3NKA), a marker of muscle spindle afferents. Across all age groups, an average of 26 ± 4% of myelinated fibers of tibial nerve and 17 ± 2% of ganglion neuronal profiles were α3NKA-positive (n = 8 per group). Subject age explained 85% of the variability in these counts. The relative frequency of α3NKA-labeled fibers/neurons starts to decline during the 5th decade of life, approaching half that of young adult values in 65-year-old subjects. At all ages, α3NKA-positive neurons were among the largest of spinal ganglia neurons. However, as compared to younger subjects, the population of α3NKA-positive neurons from advanced-age subjects showed diminished numbers of large (both moderately and strongly labeled), and medium-sized (strongly labeled) profiles. Considering the critical significance of ion transport by NKA for neuronal activity, our data suggest that functional impairment and, also, most likely atrophy and/or degeneration of muscle spindle afferents, are mechanisms underlying loss of tendon reflexes with age. The larger and more strongly α3NKA-expressing spindle afferents appear to be proportionally more vulnerable.

Protoplasmic astrocytoma with multifocal involvement: case report and radiological findings.

Protoplasmic astrocytomas are a poorly characterized and extremely rare subtype of astrocytoma. We describe the CT, MR and 18F-fludeoxyglucose positron emission tomography (FDG-PET) findings of a multifocal protoplasmic astrocytoma in a 29-year-old male with neurological deficits. He was initially diagnosed with neurosarcoidosis based on imaging. MRI demonstrated intraparenchymal lesions involving the right temporal lobe and cerebellum. These appeared as extremely hyperintense signals on T 2 weighted imaging and as homogeneous enhancements with a small non-enhancing cystic component on contrast-enhanced MR. Diffuse post-contrast enhancement of the craniospinal meninges was also noted. Post-radiation therapy PET-CT demonstrated a highly FDG-avid tumour in the right temporal lobe and left cerebellum. To our knowledge, a multifocal form of protoplasmic astrocytoma in an adult patient has not been previously described.

Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late-stage autophagic organelles.

AIMS: Granulovacuolar degeneration involves the accumulation of large, double membrane-bound bodies within certain neurones during the course of Alzheimer's disease (AD) and other adult-onset dementias. Because of the two-layer membrane morphology, it has been proposed that the bodies are related to autophagic organelles. The aim of this study was to test this hypothesis, and determine the approximate stage at which the pathway stalls in AD. METHODS: Spatial colocalization of autophagic and endocytic markers with casein kinase 1 delta, a marker for granulovacuolar degeneration (GVD) bodies, was evaluated in hippocampal sections prepared from post mortem Braak stage IV and V AD cases using double-label confocal fluorescence microscopy. RESULTS: GVD bodies colocalized weakly with early-stage autophagy markers LC3 and p62, but strongly with late-stage marker lysosome-associated membrane protein 1 (LAMP1), which decorated their surrounding membranes. GVD bodies also colocalized strongly with charged multivesicular body protein 2B (CHMP2B), which colocalized with the core granule, but less strongly with lysosomal marker cathepsin D. CONCLUSIONS: The resultant immunohistochemical signature suggests that granulovacuolar degeneration bodies (GVBs) do contain late-stage autophagic markers, and accumulate at the nexus of autophagic and endocytic pathways. The data further suggest that failure to complete autolysosome formation may be an important correlate of GVB accumulation.

Alzheimer-type neuropathological changes in morbidly obese elderly individuals.

OBJECTIVE: Middle age obesity increases risk for Alzheimer disease (AD). This study evaluated neuropathological changes in morbidly obese patients ranging in age from 21-70 years. METHODS: 12 autopsied morbidly obese patients (> or = 136 kg, BMI 45.3-81.1, 7 male, 5 female, ages 21-70), without cognitive impairment, were compared to 10 non-obese controls (52-106 kg, BMI 17.4-32.5, 8 male, 2 female, ages 29-74), and 3 AD controls (1 male, 2 female, ages 63-78). Standard hippocampal sections were stained for Bielschowsky, A beta (4G8), tau (AT8), or A beta PP (monoclonal, Pierce) and evaluated using semiquantitative criteria. RESULTS: Obese patients had normal-sized brains, but larger hearts (713 +/- 273 vs. 438 +/- 71 g, p <0.01). Only rare brain lesions were noted in any patients < 65 years. Obese patients > 65 years showed high levels of all indices, in some cases comparable to those seen in AD. Compared to non-obese, non-AD controls, the differences in tau and A beta PP expression (but not A beta) were significant (p < 0.05, Mann-Whitney U-test). CONCLUSION: Alzheimer-type neuropathological changes were frequent in our small sample of morbidly obese elderly individuals without clinical history of cognitive impairment, approaching those seen in Alzheimer disease for some patients. Such changes were not seen in younger obese patients. These changes may be attributable to comorbid conditions such as congestive heart failure, obstructive sleep apnea, or metabolic lipid abnormalities.

Neurotrophin receptors and heparanase: a functional axis in human medulloblastoma invasion.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although modern therapy has produced five-year survival rates as high as 70% for some MB patients, this resulted in significant long-term treatment-related morbidity. The cellular mechanisms involved in metastatic spread of medulloblastoma are largely unknown. Neurotrophins (NT) comprise a family of structurally and functionally related neurotrophic factors that are critical for central nervous system (CNS) development with nerve growth factor (NGF) being the prototypic NT. NT acts through two groups of structurally unrelated neurotrophin receptors (NTR): a family of receptor tyrosine kinases (Trks, mainly TrkA, TrkB, and TrkC) and a tumor necrosis factor receptor (TNFR)-like molecule called p75NTR TrkC expression is a good prognostic indicator for MB. TrkC binds only to neurotrophin-3 (NT-3) whereas p75 binds to all NT family members. Importantly, little is known about the biological functions of p75 in primitive neuroectodermal tumors such as MB. In contrast, NT-regulated heparanase (HPSE) is a unique extracellular matrix-degrading enzyme known to be associated with tumor progression in a wide variety of cancers. However, HPSE roles in MB invasive pathways have not been investigated. We provide evidence of a differential expression of HPSE in newly-developed medulloblastoma cell lines. Secondly, we show a correlation between HPSE expression and the invasive properties of these medulloblastoma lines. Thirdly, by performing investigations to elucidate prognostic implications of HPSE and TrkC/p75NTR expression in MB, we demonstrate a correlation between p75NTR and HPSE expression. Finally, by using antibodies specific to TrkC and immunohistochemistry (IHC) we prove that IHC scores reveal a significant expression of HPSE in 76% of MB tissues from children aged 3 years and older. Taken together, our data provide evidence that HPSE functionality, in a context linked to TrkC and p75NTR activation, may play critical roles in medulloblastoma tumor invasion and progression.

The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology.

Argyrophilic grain disease (AGD) constitutes a neurodegenerative disorder that occurs in the brains of the elderly and affects 5% of all patients with dementia. Tau protein-containing lesions known as argyrophilic grains and located predominantly in limbic regions of the brain characterize this disease. Dementia is encountered in only a subset of cases that display the morphological pattern of AGD. The aim of this study is to determine the role of concurrent Alzheimer's disease (AD)-related pathology for the development of dementia in AGD patients. A total of 204 post-mortem brains from 30 demented and 49 nondemented AGD patients, 39 AD patients, and from 86 nondemented controls without AGD were staged for AD-related neurofibrillary tangles (NFTs) as well as amyloid beta-protein (Abeta) deposition. To identify differences in AD-related pathology between demented and nondemented AGD cases, and to differentiate the pattern of AD-related changes in demented and nondemented AGD cases from that seen in AD and nondemented controls, we statistically compared the stages of Abeta and NFT distribution among these groups. Using a logistic regression model, we showed that AGD has a significant effect on the development of dementia beyond that attributable to AD-related pathology (P < 0.005). Demented AGD cases showed lower stages of AD-related pathology than did pure AD cases but higher stages than nondemented AGD patients. AGD associated dementia was seen in the presence of NFT (Braak)-stages II-IV and Abeta-phases 2-3, whereas those stages were not associated with dementia in the absence of AGD. In conclusion, AGD is a clinically relevant neurodegenerative entity that significantly contributes to the development of dementia by lowering the threshold for cognitive deficits in the presence of moderate amounts of AD-related pathology.

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.

Vitamin E suppression of microglial activation is neuroprotective.

Neurotoxic microglial-neuronal interactions have been implicated in the pathogenesis of various neurodegenerative diseases such as Alzheimer's disease, and vitamin E has been shown to have direct neuroprotective effects. To determine whether vitamin E also has indirect neuroprotective effects through suppression of microglial activation, we used a microglial-neuronal coculture. Lipopolysaccharide (LPS) treatment of a microglial cell line (N9) induced a time-dependent activation of both p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappaB (NFkappaB), with consequent increases in interleukin-1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production. Differentiated neuronal cells (PC12 cells treated with nerve growth factor) exhibited marked loss of processes and decreased survival when cocultured with LPS-activated microglia. Preincubation of microglia with vitamin E diminished this neurotoxic effect, independently of direct effects of the antioxidant on the neuronal cells. Microglial NO production and the induction of IL-1alpha and TNFalpha expression also were attenuated by vitamin E. Such antiinflammatory effects of vitamin E were correlated with suppression of p38 MAPK and NFkappaB activation and were mimicked by an inhibition of either p38 MAPK (by SB203580) or NFkappaB (by decoy oligonucleotides). These results suggest that, in addition to the beneficial effects of providing direct antioxidant protection to neurons reported by others, vitamin E may provide neuroprotection in vivo through suppression of signaling events necessary for microglial activation.

A unique microvascular phenotype shared by juvenile hemangiomas and human placenta.

BACKGROUND: Juvenile hemangiomas are common, benign tumors, distinctive for their perinatal presentation, rapid growth during the first year of life, and subsequent involution. We recently reported that endothelia of hemangiomas highly express GLUT1, a glucose transporter normally restricted to endothelia with blood-tissue barrier function, as in brain and placenta. OBJECTIVE: To investigate possible further similarities between hemangioma and placental vessels. DESIGN: In a retrospective study of a variety of vascular tumors and anomalies, we assessed lesional immunoreactivities for the placenta-associated vascular antigens FcgammaRII, Lewis Y antigen (LeY), merosin, and GLUT1. SETTING: A university-affiliated pediatric hospital. MAIN OUTCOME MEASURE: Immunoreactivities scored for each antigen were summarized according to lesional type, compared with those of normal skin, brain, and placenta, and correlated with patient age, sex, and lesional location. RESULTS: All of 66 hemangiomas (patients aged 22 days to 7 years) showed intense immunoreactivity for FcgammaRII, merosin, LeY, and GLUT1. No immunoreactivities for these markers were seen in any of 26 vascular malformations, 4 granulation tissue specimens, 13 pyogenic granulomas, or in the tumor vasculature of 6 malignant tumors of nonvascular origin. Microvascular immunoreactivity for all 4 markers was observed in placental chorionic villi, but was absent in microvessels of normal skin and subcutis. Brain microvessels expressed only GLUT1 and merosin. CONCLUSIONS: A distinct constellation of tissue-specific markers is uniquely coexpressed by hemangiomas and placental microvessels. These findings imply a unique relationship between hemangioma and the placenta and suggest new hypotheses concerning the origin of these tumors.

A novel, cell-specific attenuation of a herpes simplex virus type 1 infection in vivo.

We have observed a cell-specific attenuation of herpes simplex virus type 1 strain 17syn+ in vivo that was dependent upon the cell type used to grow the virus. Direct corneal infection of rabbits with 17syn+ propagated in Vero cells caused 60% (6 of 10) to develop severe central nervous system (CNS) disease as evidenced by seizures and/or paralysis; all neurologically impaired rabbits died. In contrast, infection of rabbits with 17syn+ propagated in BHK-21 cells induced seizures and was fatal in 10% (1 of 10). The cell-specific attenuation of a 17syn+ occurred after one growth cycle in BHK-21 cells. To determine whether the decreased virulence of the BHK-21 cell-grown virus correlated with a less severe CNS inflammatory reaction, CNS tissues from rabbits infected with 17syn+ grown in Vero and BHK-21 cells were compared. Histopathological analyses revealed no differences in the location or severity of inflammatory lesions from rabbits infected with virus grown in either cell type. Virus-induced corneal disease was less dependent upon the cell type used to propagate the virus as there were no significant differences in the type or severity of observed corneal lesions. Possible explanations based on differences between Vero and BHK-21 cells are discussed.

Phospholipid abnormalities in postmortem schizophrenic brains detected by 31P nuclear magnetic resonance spectroscopy: a preliminary study.

It has been hypothesized that schizophrenia arises from cell membrane abnormalities due to changes in phospholipid (PL) composition and metabolism. We have used high resolution, in vitro 31P nuclear magnetic resonance (NMR) to characterize the PLs in left frontal cortex (gray matter) of postmortem brain from four schizophrenics and five controls. High resolution 31P NMR spectra were obtained in an organic-solvent system to resolve PL classes (headgroups) and in a sodium-cholate, aqueous dispersion system to resolve phosphatidylcholine (PC) molecular species. Multivariate analysis which included the major PC molecular species and phosphatidylinositol (PI) showed a significant difference between schizophrenics and controls. Analysis of specific interactions showed that the PI was significantly higher in the schizophrenic group than in the control group. There were no differences between the two groups for other individual PL classes, or for individual PL subclasses determined by the linkage type at the sn-1 position on glycerol. There was a trend for total PL content to be higher in schizophrenics than in controls. There was no evidence for elevated lysophosphatidylcholine or lysophosphatidylethanolamine in schizophrenia. The intensity of the PC peak representing molecular species with one saturated and one unsaturated (one or two double bonds) acyl chain was higher for the schizophrenic group than for the control group. Although these results are not in complete agreement with previous studies, they support the idea that PL abnormalities occur in the brain in schizophrenia and that fatty acid metabolism may be abnormal.

Interleukin-1, neuroinflammation, and Alzheimer's disease.

Interleukin-1 (IL-1)-1) is a pluripotent immunomodulatory cytokine that has an initiating role in cellular and humoral immunity in the periphery. Il-1 is overexpressed in Alzheimer brain, and this overexpression is directly related to plaque formation and progression, nonsensical growth of dystrophic neurites, and neuronal overexpression of acetylcholinesterase. IL-1 has a number of actions relevant to Alzheimer's disease, including excessive expression of neuronal Abeta precursor protein and other plaque-associated proteins, and induction of astrocyte activation and astrocytic overexpression of S100B. These latter events may be related to the overgrowth of dystrophic neurites in neuritic plaques, a necessary event for conversion of diffuse Abeta deposits into the neuritic amyloid plaques diagnostic of Alzheimer's disease. Four new genetic studies underscore the relevance of IL-1 to Alzheimer pathogenesis, showing that homozygosity of a specific polymorphism in the IL-1A gene at least triples Alzheimer risk, especially for an earlier age of onset and in combination with homozygosity for another polymorphism in the IL-1B gene.

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 role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease.

Activated astrocytes, overexpressing the neurotrophic signaling molecule S100beta, are invariant components of the Abeta plaques of Alzheimer's disease. Even early, nonfibrillar amyloid deposits in Alzheimer's disease contain such astrocytes, and the numbers and degree of activation of these wax and wane with the subsequent neuritic pathology of plaque evolution. Astrocytic overexpression of S100B in the neuritic plaques of Alzheimer's disease correlates with the degree of neuritic pathology in Abeta plaques in this disease, suggesting a pathogenic role for S100B's neurotrophic properties in the evolution of these lesions. Astrocytic overexpression of S100B, in turn, is promoted by high levels of interleukin-1 (IL-1), originating from activated microglia that are also constant components of Abeta plaques in Alzheimer's disease. Similar patterns of astrocyte activation, S100B overexpression, microglial activation, and IL-1 overexpression are seen in conditions that confer risk for Alzheimer's disease (aging, head trauma, Down's syndrome), in conditions that predispose to accelerated appearance of Alzheimer-like neuropathologic changes (chronic epilepsy, HIV infection), and in animal models of Alzheimer's disease. These cells and molecules are an important components of a cytokine cycle of molecular and cellular cascades that may drive disease progression 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.

Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients.

BACKGROUND: We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. METHOD: We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, cAMP, and ATF-2 proteins. RESULTS: We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. CONCLUSION: Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia.

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.

Interleukin-1 and the immunogenetics of Alzheimer disease.

Established genetic causes of familial Alzheimer disease (AD) involve genes for beta-amyloid precursor protein (betaAPP), presenilin-1, and presenilin-2. For the more common sporadic forms of AD, increased risk has been associated with a number of genes; the most important of which is the epsilon4 allele of apolipoprotein E. Two recent studies, one clinical and one using postmortem material, now show increased risk for AD associated with certain polymorphisms in the genes encoding the alpha and beta isoforms of interleukin-1 (IL-1). IL-1 levels are elevated in Alzheimer brain, and overexpression of IL-1 is associated with beta-amyloid plaque progression. IL-1 interacts with the gene products of several other known or suspected genetic risk factors for AD, including betaAPP, apolipoprotein E, alpha1-antichymotrypsin, and alpha2-macroglobulin. IL-1 overexpression is also associated with environmental risk factors for AD, including normal aging and head trauma. These observations suggest an important pathogenic role for IL-1, and for IL-1-driven cascades, in the pathogenesis of AD.

Association of interleukin-1 gene polymorphisms with Alzheimer's disease.

Interleukin-1 (IL-1) is markedly overexpressed in Alzheimer's disease. We found the IL-1A 2,2 genotype in 12.9% of 232 neuropathologically confirmed Alzheimer's disease patients and 6.6% of 167 controls from four centers in the United Kingdom and United States (odds ratio, 3.0; controlled for age and for ApoE [apolipoprotein E] genotype). Homozygosity for both allele 2 of IL-1A and allele 2 of IL-1B conferred even greater risk (odds ratio, 10.8). IL-1 genotypes may confer risk for Alzheimer's disease through IL-1 overexpression and IL-1-driven neurodegenerative cascades.