Alterations in the Peripheral Immune System in Dementia

Busse, Mandy; Michler, Enrico; Hoff, F; Dobrowolny, Henrik; Hartig, Roland; Frodl, Thomas; Busse, Stefan

doi:10.3233/jad-161304

Cited by 67 publications

(64 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, this last team of authors reported that levels of activated HLA-DR-positive CD4 + and CD8 + T cells were significantly increased in the peripheral blood of AD and MCI patients compared with age-and sex-matched controls, but not in patients with a range of non-AD dementias [83]. This finding is consistent with that of other published research which indicates that the pattern of T cell abnormalities seen in AD may well be specific to the disease [87,88].…”

Section: Evidence Of Peripheral Immune Abnormalities In Adsupporting

confidence: 86%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

View full text Add to dashboard Cite

The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

show abstract

Section: Evidence Of Peripheral Immune Abnormalities In Adsupporting

confidence: 86%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

View full text Add to dashboard Cite

show abstract

“…These findings support the hypothesis that AD pathophysiology may be related to salivary levels of Lf and the innate immune response to brain infections. Innate immune pathways are commonly activated in other neurodegenerative disorders [45][46][47][48]. Therefore, it is remarkable that salivary Lf levels will not decrease in other dementia such as FTD.…”

Section: Discussionmentioning

confidence: 99%

Decreased salivary lactoferrin levels are specific to Alzheimer’s disease

González-Sánchez

Antequera

Puertas-Martín

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Efforts focused on developing new less invasive biomarkers for early Alzheimer’s disease (AD) diagnosis are substantial. Evidences of infectious pathogens in AD brains may suggest a deteriorated innate immune system in AD pathophysiology. We previously demonstrated reduced salivary levels of Lf in AD patients, one of the major antimicrobial peptides. Methods To assess the clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid-β (Aβ) load in two different cross-sectional cohorts including patients with different neurodegenerative disorders. Study participants for cohort 1 (n = 116) were enrolled from the 12 de Octubre University Hospital Neurology Service in Madrid (Spain) and Pablo de Olavide University in Sevilla (Spain). Study participants for cohort 2 (n = 142) were enrolled as part of the Atherobrain - Heart to Head (H2H) project. Participants underwent neurological and neuropsychological examination, saliva sampling, and amyloid-Positron-Emission Tomography (PET) neuroimaging. Results The diagnostic performance of salivary Lf in the cohort 1 had an area under the curve [AUC] of 0.95 (0.911-0.992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET + ) versus healthy group, and 0.97 (0.924-1) versus the frontotemporal dementia (FTD) group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0.93 (95% CI 0.876-0.989). Salivary Lf detected prodromal AD and AD dementia distinguishing them from other dementias as FTD with over 87% sensitivity and 91% specificity. Conclusion Therefore, salivary Lf seems to have a very good diagnostic performance to detect AD. Our findings support the possible utility of salivary Lf as a new non-invasive and cost-effective AD biomarker.

show abstract

“…The enhanced neuroinflammatory process damages neurons and alters the (BBB). These mediators also induce peripheral inflammation and then return to further stimulate local neuroinflammation ( Blach-Olszewska et al, 2015 ; Festoff, 2016 ; Busse et al, 2017 ). This progressive pro-inflammatory situation is exacerbated with age, creating a vicious cycle of local and systemic inflammatory responses leading to activation of cytotoxic microglia, unbalanced cytokine production, Aβ accumulation and irreversible brain damage.…”

Section: How May All These Theories Be Reconciled?mentioning

confidence: 99%

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer’s Disease?

Fülöp

Witkowski

Bourgade

et al. 2018

Front. Aging Neurosci.

158

125

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the “beta-amyloid hypothesis” that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the “infection hypothesis” was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection – Aβ – AD and discuss future possible treatments based on this paradigm.

show abstract

Alterations in the Peripheral Immune System in Dementia

Cited by 67 publications

References 47 publications

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Decreased salivary lactoferrin levels are specific to Alzheimer’s disease

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer’s Disease?

Contact Info

Product

Resources

About