Is amyloidogenesis during Alzheimer's disease due to an IL-1-/IL-6-mediated ‘acute phase response’ in the brain?

doi:10.1016/0167-5699(91)90032-O

Immunology Today

Volume 12, Issue 7, July 1991, Pages 217-219

Immunology Today

https://doi.org/10.1016/0167-5699(91)90032-O Get rights and content

Abstract

Alzheimer's disease is characterized by the presence of amyloid plaques in the brain, which comprise mainly β-amyloid peptide and α₁-antichymotrypsin. Here, Peter Vandenabeele and Walter Fiers advance the hypothesis that this amyloidogenesis results from an IL-1-/IL-6-mediated acute phase reaction in the brain. They propose possible intracerebral sources of cytokines and acute phase proteins in microglia, astrocytes, neurons and cells of the choroid plexus.

References (44)

C.R. Abraham et al.
Cell
(1988)
C.R. Abraham et al.
Neurobiol. Aging
(1990)
E.H. Koo et al.
Neuron
(1990)
S.R. Whittemore et al.
Brain Res. Rev
(1987)
C.M. Van Duijn et al.
Neurosci. Lett
(1990)
C.W. Wong et al.
B.T. Hyman et al.
Science
(1984)
P.H. St George-Hyslop et al.
Nature
(1990)
A. Goate et al.
Nature
(1991)
J. Kang et al.
Nature
(1987)

R.C.A. Pearson et al.

P.C. Heinrich et al.

Biochem J

(1990)

Cited by (255)

Precision Nutrition in Aging and Brain Health
2023, Precision Nutrition: the Science and Promise of Personalized Nutrition and Health
Precision Nutrition through genetics, epigenetics, the microbiome, and metabolomics, promises to improve personalized nutrition recommendations to maintain brain health and prevent common forms of dementia. Healthy aging is increasingly being viewed as related to many lifestyle factors that affect the rate of aging among individuals. Inflammation is associated with abdominal adiposity and overweight and is a risk factor for dementia and premature aging. Alzheimer’s and Parkinson’s dementias afflict tens of millions of people worldwide. Numerous factors, including genetics, nutrition, sleep, and exercise, affect brain health. Precision Nutrition may play a role in defining individualized recommendations for patients with early forms of these diseases, including mild cognitive impairment (MCI), and instilling lifetime habits of diet and exercise that may promote brain health and healthy brain aging.
Astrocyte subtype-specific approach to Alzheimer's disease treatment
2021, Neurochemistry International
Citation Excerpt :
Contrarily, IL-6 like cytokines may have detrimental effects on neurogenesis during development (John et al., 2005). While some data suggest that IL-6 inhibits the expression of proinflammatory cytokines like IL-1β and TNFα (John et al., 2005), others show that it may induce APP synthesis (Vandenabeele and Fiers, 1991). In AD, it may trigger ERK1/ERK2 and STAT3 (Schumann et al., 1999) as well as induce the expression of acute phase proteins including α2-macroglobulin and metallothionine in neurons (Ganter et al., 1991; Bauer et al., 1993; Akiyama et al., 2000).
Astrocytes respond to any pathological condition in the central nervous system (CNS) including Alzheimer's disease (AD), and this response is called astrocyte reactivity. Astrocyte reaction to a CNS insult is a highly heterogeneous phenomenon in which the astrocytes undergo a set of morphological, molecular and functional changes with a characteristic secretome profile. Such astrocytes are termed as ‘reactive astrocytes’. Controversies regarding the reactive astrocytes abound. Recently, a continuum of reactive astrocyte profiles with distinct transcriptional states has been identified. Among them, disease-associated astrocytes (DAA) were uniquely present in AD mice and expressed a signature set of genes implicated in complement cascade, endocytosis and aging. Earlier, two stimulus-specific reactive astrocyte subtypes with their unique transcriptomic signatures were identified using mouse models of neuroinflammation and ischemia and termed as A1 astrocytes (detrimental) and A2 astrocytes (beneficial) respectively. Interestingly, although most of the A1 signature genes were also detected in DAA, as opposed to A2 astrocyte signatures, some of the A1 specific genes were expressed in other astrocyte subtypes, indicating that these nomenclature-based signatures are not very specific. In this review, we elaborate the disparate functions and cytokine profiles of reactive astrocyte subtypes in AD and tried to distinguish them by designating neurotoxic astrocytes as A1-like and neuroprotective ones as A2-like without directly referring to the A1/A2 original nomenclature. We have also focused on the dual nature from a functional perspective of some cytokines depending on AD-stage, highlighting a number of them as major candidates in AD therapy. Therefore, we suggest that promoting subtype-specific beneficial roles, inhibiting subtype-specific detrimental roles or targeting subtype-specific cytokines constitute a novel therapeutic approach to AD treatment.
Eicosapentaenoic acid-enriched phospholipids improve Aβ1-40-induced cognitive deficiency in a rat model of Alzheimer's disease
2016, Journal of Functional Foods
Citation Excerpt :
Accordingly, IL1β and TNFα are detected in AD brains (Dickson, Lee, Mattiace, Yen, & Brosnan, 1993; Goldgaber et al., 1989). These cytokines might be involved in the pathogenesis of AD, for example, by promoting local inflammatory responses (Vandenabeele & Fiers, 1991). An increasing body of research suggests that CNS inflammation, mediated by glial activation and the production of inflammatory mediators such as cytokines and complement proteins, plays a role in the pathophysiology of AD (Benveniste, Tang, & Law, 1995).
Abundant studies have proven that the protective effects of omega-3 polyunsaturated fatty acids enriched phospholipids (n-3 PUFA-PLs) mainly derived from fish roe and Antarctic krill have beneficial effects on cognition. However, the n-3 PUFA-PLs are usually a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) enriched phospholipids. Hence, the effects of EPA-PLs alone on cognitive deficiency are still unclear. In the present study, we obtained almost pure EPA-PLs (EPA:DHA = 47.9:2.08) from the sea cucumber, Cucumaria frondosa, and investigated its effects on Aβ-induced cognitive impairment in rats. Administration of EPA-PLs (150 and 300 mg/kg⋅day, i.g., 27 days) did not increase brain DHA but significantly improved Aβ-induced cognitive deficiency. Further mechanism research indicated that EPA-PLs alleviated Aβ-induced neurotoxicity including oxidative stress, apoptosis, neuro-inflammation cascade, and hyper-phosphorylated tau in a dose-dependent pattern. These findings first suggest that EPA-PLs could also improve Aβ induced cognitive deficiency in a similar mechanism with DHA-PLs.
Emerging roles of the γ-secretase-notch axis in inflammation
2015, Pharmacology and Therapeutics
Citation Excerpt :
Indeed, evidence suggests a central role of inflammation in the development of AD. For example, levels of pro-inflammatory cytokines such as TNF, IL-1, IL-6, and IL-18 are increased in various regions of the AD brain (Bauer et al., 1991; Cacabelos et al., 1994; Ojala et al., 2009; Vandenabeele & Fiers, 1991). Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), IL-6, and IL-8 has been found to be higher in the brain of the PS1 mutant AD patients (Sokolova et al., 2009), indicating a link between PS1/γ-secretase and inflammation in AD.
γ-Secretase is a distinct proteolytic complex required for the activation of many transmembrane proteins. The cleavage of substrates by γ-secretase plays diverse biological roles in producing essential products for the organism. More than 90 transmembrane proteins have been reported to be substrates of γ-secretase. Two of the most widely known and studied of these substrates are the amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β (Aβ) and the Notch intracellular domain (NICD), respectively. The wide spectrum of γ-secretase substrates has made analyses of the pathology of γ-secretase-related diseases and underlying mechanisms challenging. Inflammation is an important aspect of disease pathology that requires an in-depth analysis. γ-Secretase may contribute to disease development or progression by directly increasing and regulating production of pro-inflammatory cytokines. This review summarizes recent evidence for a role of γ-secretase in inflammatory diseases, and discusses the potential use of γ-secretase inhibitors as an effective future treatment option.
Is there an association between peripheral immune markers and structural/functional neuroimaging findings?
2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
For example, elevated levels of interleukin-1β (IL-1β) are observed in patients with mild cognitive impairment (MCI), specifically in those with impairment in multiple cognitive domains (Forlenza et al., 2009). Also, interleukin-6 (IL-6) is strongly associated with AD senile plaques (Strauss et al., 1992) and there is evidence suggesting that amyloid plaque formation in AD might be mediated by interleukin-1 (IL-1)/IL-6 acute phase reaction (Vandenabeele and Fiers, 1991). More specifically, in AD, expression of IL-6 is increased in the parietal cortex and decreased in the temporal cortex, occipital cortex and cerebellum compared to age matched controls.
There is mounting evidence that inflammatory processes play a key role in emotional as well as cognitive dysfunctions. In this context, research employing magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MR spectroscopy) suggests a possible link between structural/functional anomalies in the brain and an increase of circulating inflammation markers. The present paper reviews this research, with particular focus on major depressive disorder (MDD), cognitive impairment in older adults, Alzheimer's disease (AD) and schizophrenia.
In MDD, cognitive impairment and AD, inflammatory processes have been found to be associated with both structural and functional anomalies, perhaps under the influence of environmental stress. Not enough research can suggest similar considerations in schizophrenia, although studies in mice and non-human primates support the belief that inflammatory responses generated during pregnancy can affect brain development and contribute to the etiology of schizophrenia.
The present review suggests a link between inflammatory processes and MRI detected anomalies in the brain of individuals with MDD, older adults with cognitive impairment as well as of individuals with AD and schizophrenia.
Multiplex analysis of intrathecal cytokines in patients with mild cognitive impairment
2011, Revista del Laboratorio Clinico
El estudio del papel de las citoquinas en los procesos neuroinmunológicos se ha intensificado en la última década, si bien los resultados han sido contradictorios debido al empleo de tecnologías poco sensibles. La implementación de la tecnología Multiplex en los inmunoensayos puede ser beneficiosa en la evaluación de pacientes con daño cognitivo leve (DCL) que evolucionan a enfermedad de Alzheimer (EA).
Treinta y siete pacientes con DCL y 24 sujetos control fueron estudiados mediante análisis Multiplex de citoquinas intratecales y en suero. Las variables del estudio fueron las citoquinas IL1β, IL2, IL5, IL6, IL7, IL8, IL10, IL12p70, IL13, factor necrosis tumoral alfa (TNFα), interferón gamma (IFNγ) y factor de crecimiento de granulocito-macrófago (GM-CSF) y los cocientes pro/antiinflamatorios IL6/IL10, IL6/IL5, IL8/IL10, IL8/IL5, TNFα/IL10 y TNFα/IL5. Se estudió la evolución a EA en los pacientes DCL y en los sujetos control en el período de un año.
Se encontraron diferencias significativas (p < 0,05) para el cociente IL6/IL10 entre el grupo DCL y el grupo control (mediana [rango intercuartílico]): (1,39 [1,18-1,80] vs. 1,91 [2,68-1,18] pg/ml). De 37 pacientes con DCL, 14 evolucionaron a EA (DCL-EA) en el período de un año. De nuevo se encontraron diferencias significativas (p < 0,05) en el cociente IL6/IL10 entre el grupo DCL-EA y DCL- S (o estable): (1,29 [0,84-1,56] vs. 1,42 [1,27-2,07] pg/ml). Ninguno de los sujetos control evolucionó a EA.
El descenso en el cociente IL6/IL10 en LCR puede ser un prometedor marcador diagnóstico de DCL y predictor/pronóstico de EA en DCL.
There has been an increase in the number of studies on the role of cytokines in neuro-immunological processes, over the last ten years, but some of these results have been contradictory due to a lack of sensitivity in the technology. The new Multiplex immunoassays can be beneficial for monitoring Mild Cognitive Impairment (MCI) patients who progress to Alzheimer Disease (AD).
A study was conducted on 37 MCI patients and 24 control subjects by means of multiplex analysis of CSF cytokines. The variables measured were the following cytokines: IL1β, IL2, IL5, IL6, IL7, IL8, IL10, IL12p70, IL13, tumour necrosis factor alpha (TNFα), interferon gamma (IFNγ) and granulocyte – macrophage growth colony stimulating factor (GM-CSF), as well as the following pro/anti-inflammatory ratios: IL6/IL10, IL6/IL5, IL8/IL10, IL8/IL5, TNFα/IL10 and TNFα/IL5. Progress to AD in MCI patients was studied over a period of one year.
Significant differences were found (P < .05) for IL6/IL10 ratio between MCI patients and Control group (median [IR]): (1.39 [1.18-1.80] vs. 1.91 [2.68-1.18] pg/mL). Of the 37 MCI patients, 14 progressed to AD (DCL-EA group) within a year. Significant differences were also found (P < .05) for IL6/IL10 ratio between the DCL-EA group and the rest of MCI patients that did not progress (DCL-S or stable): (1.29 [0.84-1.56] vs. 1.42 [1.27-2.07] pg/mL). None of the control subjects progressed to AD.
A decrease in CSF IL6/IL10 ratio could be a promising diagnostic biomarker in MCI and a prognostic biomarker of AD in MCI.

View all citing articles on Scopus

^☆: Research in the authors' laboratory was supported by the Belgian FGWO, IUAP, ASLK and the National Lottery.

^∗: We thank E. Van Mechelen for fruitful discussion and M. Vandecasteele for editorial assistance.

View full text

ViewpointIs amyloidogenesis during Alzheimer's disease due to an IL-1-/IL-6-mediated ‘acute phase response’ in the brain?☆

Abstract

Cell

Neurobiol. Aging

Neuron

Brain Res. Rev

Neurosci. Lett

Science

Nature

Nature

Nature

Science

Nature

Nature

Nature

Nature

Nature

Science

Science

Science

Bio/Technology

Biochem J

Viewpoint
Is amyloidogenesis during Alzheimer's disease due to an IL-1-/IL-6-mediated ‘acute phase response’ in the brain?☆