Systemic and Central Immunity in Alzheimer's Disease: Therapeutic Implications

Butchart, Joe; Holmes, Clive

doi:10.1111/j.1755-5949.2011.00245.x

Cited by 31 publications

(21 citation statements)

References 208 publications

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“…It is well accepted that neuroinflammation occurs in AD, with infiltrates of T-lymphocytes and monocytes that are responsible, together with microglia cells, for the increase in a number of cytokines in the CNS [38][39][40]. Systemic inflammation also exists in AD patients, with the production of a number of interleukins and other cytokines that are increased in peripheral blood many years before the initiation of cognitive decline [41,42]. In this context, increased levels of IL-1␣, IFN-␥, TNF-␣ and reactive C protein have been described in fungal infections and in AD peripheral blood and CNS after microglia activation [36,37,40,[43][44][45].…”

Section: Discussionmentioning

confidence: 96%

Direct Visualization of Fungal Infection in Brains from Patients with Alzheimer's Disease

Pisa

Alonso

Juarranz

et al. 2014

JAD

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Recently, we have reported the presence of fungal infections in patients with Alzheimer's disease (AD). Accordingly, fungal proteins and DNA were found in brain samples, demonstrating the existence of infection in the central nervous system. In the present work, we raised antibodies to specific fungal species and performed immunohistochemistry to directly visualize fungal components inside neurons from AD patients. Mice infected with Candida glabrata were initially used to assess whether yeast can be internalized in mammalian tissues. Using polyclonal rabbit antibodies against C. glabrata, rounded immunopositive cells could be detected in the cytoplasm of cells from liver, spleen, and brain samples in infected, but not uninfected, mice. Immunohistochemical analyses of tissue from the frontal cortex of AD patients revealed the presence of fungal material in a small percentage (~10%) of cells, suggesting the presence of infection. Importantly, this immunopositive material was absent in control samples. Confocal microscopy indicated that this fungal material had an intracellular localization. The specific morphology of this material varied between patients; in some instances, disseminated material was localized to the cytoplasm, whereas small punctate bodies were detected in other patients. Interestingly, fungal material could be revealed using different anti-fungal antibodies, suggesting multiple infections. In summary, fungal infection can only be observed using specific anti-fungal antibodies and only a small percentage of cells contain fungi. Our findings provide an explanation for the hitherto elusive detection of fungi in AD brains, and are consistent with the idea that fungal cells are internalized inside neurons.

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Section: Discussionmentioning

confidence: 96%

Direct Visualization of Fungal Infection in Brains from Patients with Alzheimer's Disease

Pisa

Alonso

Juarranz

et al. 2014

JAD

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“…; Sardi et al . ; Butchart & Holmes ; Rubio‐Perez & Morillas‐Ruiz ; Wyss‐Coray & Rogers ; McGeer & McGeer ; Medeiros & LaFerla ; Meraz‐Rios et al . ; Wilcock & Griffin ; Cherry et al .…”

Section: Introductionunclassified

“…Neuroinflammation from aberrantly activated glia is reemerging as an important mechanism that contributes to AD progression (for review Akiyama et al 2000;Griffin & Mrak 2002;Eikelenboom & van Gool 2004;Van Eldik et al 2007;Landreth 2009;Tobinick 2009;Vitek et al 2009;Bachstetter & Van Eldik 2010;Gorelick 2010;Imbimbo et al 2010;Ferretti & Cuello 2011;Keene et al 2011;Sardi et al 2011;Butchart & Holmes 2012;Rubio-Perez & Morillas-Ruiz 2012;Wyss-Coray & Rogers 2012;McGeer & McGeer 2013;Medeiros & LaFerla 2013;Meraz-Rios et al 2013;Wilcock & Griffin 2013;Cherry et al 2014;Nuzzo et al 2014). The initial observations of activated microglia and astrocytes in pathologically relevant AD brain regions (Griffin et al 1989), including within and surrounding amyloid plaques (Perlmutter et al 1990;Edison et al 2008), are now complemented by recent genome-wide association studies and experimental data suggesting that several AD-genetic risk factors function through modulating neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

APOE‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective

Tai

Ghura

Koster

et al. 2015

Journal of Neurochemistry

130

118

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Chronic glial activation and neuroinflammation induced by the amyloid-b peptide (Ab) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Ab-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Ab-independent neuroinflammation, data for APOE-modulated Ab-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Ab-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38a) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation.

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“…A large body of data supports a central role for neuroinflammation in AD neuropathology and Aβ as the source of AD-associated inflammation [4,6]. Given that inflammatory response in the immunologically privileged CNS is mediated by the innate immune system, our data raise the possibility that rather than Aβ acting as a sole independent initiator of neuroinflammation, increased Aβ may trigger dysregulation of the innate immune system through depletion of extracellular S100A9 release from monocytes and decrease of its antimicrobial activity to protect against invading microbes.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive innate immune gene activation reflecting chronic innate immune activation could accompany brain aging, increasing vulnerability to cognitive decline and neurodegeneration, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages of AD [5]. Thus, clinical pharmaceutical trials aimed at modulating the immune system in AD have largely focused on dampening down central proinflammatory innate immunity and the manipulation of systemic immunity, and its communication with the central nervous system (CNS) [6]. …”

Section: Introductionmentioning

confidence: 93%

Amyloid-β peptide-induced extracellular S100A9 depletion is associated with decrease of antimicrobial peptide activity in human THP-1 monocytes

Lee

Yang

Chang

et al. 2013

J Neuroinflammation

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BackgroundS100A9 protein (myeloid-related protein MRP14, also referred to as calgranulin B) is a reliable marker of inflammation, an important proinflammatory factor of innate immunity and acts as an additional antimicrobial peptide in the innate immune system. Evidence indicates that S100A9 contributes to Alzheimer’s disease (AD) pathology, although the precise mechanisms are not clear.MethodsWe were interested to study the mechanisms of S100A9 release upon Aβ1-42 stimulation, the potential roles of extracellular S100A9 depletion in Aβ-induced cytotoxicity, and the interaction with innate immune response in THP-1 monocytic cells that have been challenged with mostly Aβ1-42 monomers instead of oligomers. We used protein preparation, Ca2+ influx fluorescence imaging, MTT assay, siRNA knockdown, colony forming units (CFUs) assay and western blotting techniques to perform our study.ResultsAβ1-42 monomers elicited a marked decrease of S100A9 release into the cell culture supernatant in a dose-dependent manner in human THP-1 monocytes. This reduction of S100A9 release was accompanied by an increase of intracellular Ca2+ level. Aβ1-42-mediated decrease of S100A9 release was not associated with Aβ1-42-induced cytotoxicity as measured by MTT reduction assay. This observation was confirmed with the recombinant S100A9, which had little effect on Aβ1-42-induced cytotoxicity. Moreover, depletion of S100A9 with siRNA did not significantly evoke the cell toxicity. On the other hand, Aβ1-42-induced extracellular S100A9 depletion resulted in decreased antimicrobial activity of the culture supernatant after Aβ1-42 stimulation. Immunodepletion of S100A9 with anti-S100A9 also decreased the antimicrobial peptide activity of the vehicle treated culture supernatant. Consistently, the recombinant S100A9 clearly elicited the antimicrobial peptide activity in vitro, confirming the observed antimicrobial activity of S100A9 in the culture supernatant.ConclusionCollectively, our findings suggest that the mostly monomeric form of Aβ1-42 negatively regulates the innate immune system by down-regulating the secretion of S100A9, which is likely a main mediator of antimicrobial activity in the conditioned media of human THP-1 monocytes.

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Systemic and Central Immunity in Alzheimer's Disease: Therapeutic Implications

Cited by 31 publications

References 208 publications

Direct Visualization of Fungal Infection in Brains from Patients with Alzheimer's Disease

Direct Visualization of Fungal Infection in Brains from Patients with Alzheimer's Disease

APOE‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective

Amyloid-β peptide-induced extracellular S100A9 depletion is associated with decrease of antimicrobial peptide activity in human THP-1 monocytes

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