W. S. T. Griffin

Inflammation and Alzheimer’s disease

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimers disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

Glial‐Neuronal Interactions in Alzheimer's Disease: The Potential Role of a ‘Cytokine Cycle’ in Disease Progression

The role of glial inflammatory processes in Alzheimers 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 β‐amyloid precursor protein, thus favoring continuing deposition of β‐amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100β, 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 Alzheimers disease.

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

Abstract 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-1α-immunoreactive (IL-1α+) 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-1α mRNA in an additional 11 neurologically normal individuals aged 1 day to 78 years. IL-1α+ 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) μm2/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-1α+ microglia. Among microglial subtypes, there were significant increases in the numbers of enlarged (threefold) and especially phagocytic (elevenfold), but not primed, microglia. Tissue IL-1α 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.

Glial-Neuronal Interactions in Alzheimer Disease: Progressive Association of IL-1α+ Microglia and S100β+ Astrocytes with Neurofibrillary Tangle Stages

Activated microglia, overexpressing interleukin-1 (IL-1), and activated astrocytes, overexpressing S100β, have been implicated in the formation and evolution of tau2-immunoreactive (tau2+) neuritic plaques in Alzheimer disease. In this study, we assessed the role of IL-lα+ microglia and S100β+ astrocytes in the pathogenesis of another cardinal histopathological feature of Alzheimer disease: tau2+ neurofibrillary tangles. Four distinct stages of neurofibrillary tangle formation were identified: neurons with granular perikaryal tau2 immunoreactivity (stage 0): fibrillar neuronal inclusions (stage 1); dense, neuronal soma-filling inclusions (stage 2); and acellular, fibrillar deposits (stage 3. “ghost tangles”). The numbers of tangles in randomly selected fields of parahippocampal cortex from II Alzheimer patients correlated with both the numbers of IL-1α+ microglia and the numbers of S100β+ astrocytes in these fields (r = 0.72, p < 0.02; r = 0.73, p = 0.01, respectively). There were progressive increases in frequency of association between tangle stages and both IL-1α+ microglia and S100β+ astrocytes: 48. 56, 67, and 92% of stage 0–3 tangles, respectively, had associated IL-1α+ microglia and 21, 37, 55, and 91% of stage 0–3 tangles had associated S100β+ astrocytes. This progressive association of activated IL-1α+ microglia and activated S100β+ astrocytes with tau2+ tangle stages suggests a role for glial-neuronal interactions in the degeneration of tangle-bearing neurons in Alzheimer disease.

Microglial inter leukin-1α expression in brain regions in Alzheimer's disease: correlation with neuritic plaque distribution

Interleukin‐1α‐immunoreactive (IL‐1α+) microglia are prominent components of neuritic plaques in Alzheimers disease, and may be important in the evolution of neuritic plaques from diffuse amyloid deposits. Neuritic plaques show a characteristic distribution across cerebral regions and are absent in the cerebellum of patients with Alzheimers disease. We used single‐ and dual‐immunohistochemical labelling to investigate the possibility that the expression of IL‐1α is correlated with this regional distribution of neuritic (tau 2‐immunoreactive, tau 2+) plaques. In Alzheimers disease, tau 2+ neuritic plaques occurred with increasing frequency in grey matter of frontal and occipital lobes, temporal lobe, and hippocampus. There were positive correlations between the regional patterns of distribution of activated IL‐1α+ microglia and tau2+ neuritic plaques as well as between activated IL‐1α+ microglia and activated astrocytes. No activated IL‐1α+ microglia, tau 2+ neuritic plaques, or activated astrocyies were observed in cerebellum of these Alzheimer patients. These regional relationships between activated IL‐1α+ microglia, tau 2+ neuritic plaques, and activated astrocytes, together with the established functions of IL‐1, support a causal association between the overexpression of IL‐1 and the evolution of β‐amyloid deposits into neuritic plaques in Alzheimers disease.

Life-long overexpression of S100β in Down’s syndrome: implications for Alzheimer pathogenesis

Chronic overexpression of the neurite growth-promoting factor S100beta has been implicated in the pathogenesis of neuritic plaques in Alzheimers disease. Such plaques are virtually universal in middle-aged Downs syndrome, making Downs a natural model of Alzheimers disease. We determined numbers of astrocytes overexpressing S100beta, and of neurons overexpressing beta-amyloid precursor protein (beta-APP), and assayed for neurofibrillary tangles in neocortex of 20 Downs syndrome patients (17 weeks gestation to 68 years). Compared to controls, there were twice as many S100beta-immunoreactive (S100beta+) astrocytes in Downs patients at all ages: fetal, young, and adult (p = 0.01, or better, in each age group). These were activated (i.e., enlarged), and intensely immunoreactive, even in the fetal group. There were no neurofibrillary changes in fetal or young Downs patients. The numbers of S100beta+ astrocytes in young and adult Downs patients correlated with the numbers of neurons overexpressing beta-APP (p < 0.05). Our findings are consistent with the idea that conditions--including Downs syndrome--that promote chronic overexpression of S100beta may confer increased risk for later development of Alzheimers disease.

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‐1α‐immunoreactive (IL‐1α+ ) 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‐1α+ microglia were similar in Alzheimer and control patients. For layers III–VI, the numbers of IL‐1α+ 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‐1α+ 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‐1α+ microglia in Alzheimer patients correlated with the cortical laminar distribution of β‐amyloid precursor protein‐immunoreactive (β‐APP+ ) neuritic plaques found in Alzheimer patients (r=0.99, P<0.005). Moreover, the cortical laminar distribution of IL‐1α+ microglia in control patients also correlated with the cortical laminar distribution of β‐APP+ neuritic plaques found in Alzheimer patients (r=0.91, P<0.05). These correlations suggest that pre‐existing laminar distribution patterns of IL‐1α+ microglia (i.e. that seen in control patients) are important in determining the observed laminar distribution of β‐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.

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.

The neuroinflammatory response in humans after traumatic brain injury.

Traumatic brain injury is a significant cause of morbidity and mortality worldwide. An epidemiological association between head injury and long‐term cognitive decline has been described for many years and recent clinical studies have highlighted functional impairment within 12 months of a mild head injury. In addition chronic traumatic encephalopathy is a recently described condition in cases of repetitive head injury. There are shared mechanisms between traumatic brain injury and Alzheimers disease, and it has been hypothesized that neuroinflammation, in the form of microglial activation, may be a mechanism underlying chronic neurodegenerative processes after traumatic brain injury.

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 Alzheimers disease. This increase is associated with earlier age of onset. Homozygosity for this polymorphism plus another in the IL-1B gene further increases risk.