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Amyloid β: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer's disease.

ABSTRACT: This review concerns how the primary inflammation preceding the generation of certain key damage-associated molecular patterns (DAMPs) arises in Alzheimer's disease (AD). In doing so, it places soluble amyloid β (Aβ), a protein hitherto considered as a primary initiator of AD, in a novel perspective. We note here that increased soluble Aβ is one of the proinflammatory cytokine-induced DAMPs recognized by at least one of the toll-like receptors on and in various cell types. Moreover, Aβ is best regarded as belonging to a class of DAMPs, as do the S100 proteins and HMBG1, that further exacerbate production of these same proinflammatory cytokines, which are already enhanced, and induces them further. Moreover, variation in levels of other DAMPs of this same class in AD may explain why normal elderly patients can exhibit high Aβ plaque levels, and why removing Aβ or its plaque does not retard disease progression. It may also explain why mouse transgenic models, having been designed to generate high Aβ, can be treated successfully by this approach.

SUBMITTER: Clark IA

PROVIDER: S-EPMC4523330 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Amyloid β: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer's disease.

Clark I A IA Vissel B B

British journal of pharmacology 20150629 15

This review concerns how the primary inflammation preceding the generation of certain key damage-associated molecular patterns (DAMPs) arises in Alzheimer's disease (AD). In doing so, it places soluble amyloid β (Aβ), a protein hitherto considered as a primary initiator of AD, in a novel perspective. We note here that increased soluble Aβ is one of the proinflammatory cytokine-induced DAMPs recognized by at least one of the toll-like receptors on and in various cell types. Moreover, Aβ is best r ...[more]

PMID: 25939581

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Project description:BackgroundDown syndrome (DS), caused by chromosome 21 trisomy, is associated with an ultra-high risk of dementia due to Alzheimer's disease (AD), driven by amyloid precursor protein (APP) gene triplication. Understanding relevant molecular differences between those with DS, those with sporadic AD (sAD) without DS, and controls will aid in understanding AD development in DS. We explored group differences in plasma concentrations of amyloid-β peptides and tau (as their accumulation is a characteristic feature of AD) and cytokines (as the inflammatory response has been implicated in AD development, and immune dysfunction is common in DS).MethodsWe used ultrasensitive assays to compare plasma concentrations of the amyloid-β peptides Aβ40 and Aβ42, total tau (t-tau), and the cytokines IL1β, IL10, IL6, and TNFα between adults with DS (n = 31), adults with sAD (n = 27), and controls age-matched to the group with DS (n = 27), and explored relationships between molecular concentrations and with age within each group. In the group with DS, we also explored relationships with neurofilament light (NfL) concentration, due to its potential use as a biomarker for AD in DS.ResultsAβ40, Aβ42, and IL1β concentrations were higher in DS, with a higher Aβ42/Aβ40 ratio in controls. The group with DS showed moderate positive associations between concentrations of t-tau and both Aβ42 and IL1β. Only NfL concentration in the group with DS showed a significant positive association with age.ConclusionsConcentrations of Aβ40 and Aβ42 were much higher in adults with DS than in other groups, reflecting APP gene triplication, while no difference in the Aβ42/Aβ40 ratio between those with DS and sAD may indicate similar processing and deposition of Aβ40 and Aβ42 in these groups. Higher concentrations of IL1β in DS may reflect an increased vulnerability to infections and/or an increased prevalence of autoimmune disorders, while the positive association between IL1β and t-tau in DS may indicate IL1β is associated with neurodegeneration. Finally, NfL concentration may be the most suitable biomarker for dementia progression in DS. The identification of such a biomarker is important to improve the detection of dementia and monitor its progression, and for designing clinical intervention studies.

Dataset Information

Amyloid β: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer's disease.

Publications

Amyloid β: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer's disease.

Similar Datasets

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