A Meta-Analysis of Cytokines in Alzheimer's Disease

Swardfager, Walter; Lanctôt, Krista L.; Rothenburg, Lana S.; Wong, Amy P.; Cappell, Jaclyn; Herrmann, Nathan

doi:10.1016/j.biopsych.2010.06.012

Cited by 890 publications

(643 citation statements)

References 194 publications

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“…7,8 By contrast, no such correlation was found between polymorphisms in genes encoding APP or γ-secretase and incidence of late-onset AD. 9 Together with the observation that inflammatory mediators are abundantly present in affected brain areas 10,11 and plasma of patients with AD, 12 these newly identified risk factors imply that alterations in innate immunity might have a key role in the disease aetiology, rather than being a passive reaction to Aβ-related neuropathology.…”

Section: Introductionmentioning

confidence: 98%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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Section: Introductionmentioning

confidence: 98%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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“…25 For example, Graham and co-workers achieved the sensitive detection of tumor necrosis factor a (TNF-a) with resonance Raman (RR) spectroscopy. 26 In the present study, interleukin-6 (IL-6) was chosen as a representative cytokine target because it is an inammatory cytokine relevant to many disease processes 27 such as diabetes, 28 Alzheimer's disease, 29 prostate cancer 30 and rheumatoid arthritis. 31 It has been reported that advanced/ metastatic cancer patients have higher median levels of IL-6 in their blood (14.8 pg mL À1 vs. 3.7 pg mL À1 ).…”

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confidence: 99%

Microspectroscopic SERS detection of interleukin-6 with rationally designed gold/silver nanoshells

Wang

Salehi

Schütz

et al. 2013

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Rationally designed gold/silver nanoshells (Au/Ag-NS) with plasmon resonances optimized for red laser excitation in order to minimize autofluorescence from clinical samples exhibit scattering cross-sections, which are ca. one order of magnitude larger compared with solid quasi-spherical gold nanoparticles (Au-NPs) of the same size. Hydrophilic stabilization and sterical accessibility for subsequent bioconjugation of Au/Ag-NS is achieved by coating their surface with a self-assembled monolayer (SAM) of rationally designed Raman reporter molecules comprising terminal mono-and tri-ethylene glycol (EG) spacers, respectively. The stability of the hydrophilically stabilized metal colloid was tested under different conditions. In contrast to metal colloids coated with a SAM without terminal EG spacers, the hydrophilically stabilized SERS particles do not aggregate under physiologically relevant conditions, i.e., buffer solutions with high ionic strength. Using these rationally designed SERS particles in conjunction with a microspectroscopic acquisition scheme, a sandwich immunoassay for the sensitive detection of interleukin-6 (IL-6) was developed. Several control experiments demonstrate the high specificity of the assay towards IL-6, with a lowest detectable concentration of ca. 1 pg mL À1 . The signal strength of the Au/Ag-NS is at least one order of magnitude higher compared with hydrophilically stabilized, non-aggregated solid quasi-spherical Au-NPs of the same size.

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“…During the last 2 decades, TNF has been implicated in numerous diseases such as arthritis, 17 Alzheimer disease, 28 cancer, 29 major depression, 30 septic shock, 31 and inflammatory bowel disease. 32 Therefore, anti-TNF therapy has been used in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

The Physiological Role of Tumor Necrosis Factor in Human Immunity and Its Potential Implications in Spinal Manipulative Therapy: A Narrative Literature Review

Zhang

Yao

2016

Journal of Chiropractic Medicine

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Objective: Although tumor necrosis factor (TNF) is a well-known inflammatory cytokine in the pathological development of various human diseases, its physiological roles are not widely understood nor appreciated. The molecular mechanisms underlying spinal manipulation therapy (SMT) remain elusive. The relationship between TNF and SMT is unclear. Thus, we performed this literature review to better understand TNF physiology and its potential relationship with SMT, and we propose a novel mechanism by which SMT may achieve clinical benefits by using certain beneficial features of TNF. Methods: We searched several databases for relevant articles published between 1975 and 2015 and then reexamined the studies from current immunophysiological perspectives. Results: The history and recent progresses in TNF physiology research were explored. Conflicting reports on the relationship between TNF and SMT were identified. Based on the newly discovered interaction between TNF and regulatory T cells, we proposed a putative biphasic TNF response to SMT, which may resolve the conflicts in the reported observations and interpretations. Conclusion: The current literature about TNF informed our discussion of new physiological roles for TNF, which may help to better understand the physiological effects of SMT. (J Chiropr Med 2016;15:190-196)

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A Meta-Analysis of Cytokines in Alzheimer's Disease

Cited by 890 publications

References 194 publications

Deciphering the mechanism underlying late-onset Alzheimer disease

Deciphering the mechanism underlying late-onset Alzheimer disease

Microspectroscopic SERS detection of interleukin-6 with rationally designed gold/silver nanoshells

The Physiological Role of Tumor Necrosis Factor in Human Immunity and Its Potential Implications in Spinal Manipulative Therapy: A Narrative Literature Review

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