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Pro-inflammatory cytokines make the blood-brain barrier more porous, allowing peripheral immune cells to enter the brain.
Beta-amyloid plaques trigger the microglial cells to release chemokines such as Macrophage inflammatory protein-1 (MIP-1) and IL-1 , IL-6 and TNF-alfa. Chemokines and cytokines, in turn, stimulate the release of cytokines, chemokines, and acute phase proteins from astrocytes, thereby activating microglial cells .
High levels of peripheral immune cells in patients with Alzheimer’s Disease (AD) are clearly involved in local inflammation.
The activation of NLRP3 and Senescence-Associated Secretory Phenotype (SASP)) factors from Senescent cells / Cellular senescence induce the release of pro-inflammatory cytokines. The NLRP3-activation comes from different Alarmins / Damage-associated molecular pattern (DAMPs): Amyloid-beta (Aß, Abeta) / Amyloid Plaques, extracellular ATP, mitochondrial DNA (mtDNA), mitochondrial reactive oxygen species (mtROS), and senescent cells. This culminates in neuroinflammation, neuronal apoptosis, and neurodegeneration
As the disease progresses, sustained TLR2 and TLR4 activation induces extensive neuroinflammation, leading to severe neurotoxic effects
Compared to age-matched controls, cognitively impaired and Alzheimer's Disease (AD) patients have a different extracellular vesicles profile including increased levels of pro-inflammatory cytokines (i.e., Pro-Interleukin-1 (IL-1) beta (IL-1 beta), IL-6, IL-10, TNF-alfa)
The development of neuroinflammation paralleled by the accumulation of toxic amyloid is followed by dysfunction of synaptic transmission, neurodegeneration , and memory and Cognitive impairment.
The concurrence of neuroinflammation and amyloid -beta dyshomeostasis, which by reciprocal interactions drive the vicious cycle of neurodegeneration, contradicts amyloid-beta as the primary trigger of Alzheimer's Disease (AD)
OMV derived from Alzheimer's Disease (AD) patients can cross the Blood Brain Barrier (BBB), promote microglia activation and inflammation, promote tau hyper-phosphorylation, and impair cognitive function when administered to wild-type mice
Priming of the inflammasome occurs when the transcription factor, NFKB, is activated, triggering the production of both NLRP3 and Pro-Interleukin-1 (IL-1) beta (IL-1 beta). NFKB can be activated via the TLR/IL-1R MyD88-dependent pathway and the C3/C5 MAPK pathway. The TLR pathway can be induced by a bacterial component, such as LPS, and the MAPK pathway can be induced by C3a/C5a binding to their respective receptors. The activation of NFKB through complement, TLR and IL-1R pathways may create a synergistic increase in pro-inflammatory factors. Aggregated fibrillary amyloid beta engulfed by the microglia can damage the lysosome and leak into the cytoplasm, also contributing to the activation of the inflammasome. Activation of the inflammasome can induce pyroptosis, leading to the secretion of IL-1 beta and ASC specks. ASC specks bind to amyloid beta and seed the surrounding parenchyma leading to further Aβ aggregation. Aggregated Aβ can also bind to TLR and induce activation of the MyD88 pathway. Likewise, IL-1β secreted from the pyroptotic microglia can bind to IL-1R and induce activation of the MyD88 pathway. The induction of the MyD88 pathway through the by-products of microglial pyroptosis may lead to a vicious cycle of inflammasome priming, inflammasome activation and pyropotosis that will exacerbate Aβ pathology.
Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Amyloid beta accumulation, synapse loss, and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement, and inflammasome signaling pathways
Pro-inflammatory cytokines such as interleukin IL-17A and IL-22 can cross the blood brain barrier (BBB), trigger immune activity, and participate in chronic neurodegenerative disease such as Alzheimer's Disease (AD)
Also, an infection could probably exaggerate neuroinflammation, promote beta-amyloid production, and then result in worsening cognitive impairment
Besides microglial activation, infiltrating peripheral CD4+ T helper cells, CD8+ Cytotoxic T Lymphocytes (CTLs) and CD4+ Th17 cells with the release of inflammatory cytokines contribute to AD-associated neuroinflammation
Alzheimer's Disease (AD) patients have a significantly different metabolite profile within in bacterial OMV (e.g., L-aspartate , L-glutamate )
The neuroinflammation hypothesis of Alzheimer's Disease (AD) focuses on the innate immune response triggered by binding of misfolded and aggregated proteins to pattern recognition receptors on microglia and astroglia, which determines the release of inflammatory mediators contributing to disease progression and severity
This will initially manifest itself in impaired hippocampal-dependent learning in Alzheimer’s Disease (AD) patients
It remains unknown which types of infiltrated immune cells are functionally involved in the development of Alzheimer’s Disease (AD)
Neuroinflammation, marked by activated microglia and astrocytes, is a common feature of Alzheimer's disease (AD), producing pro-inflammatory cytokines like Tumor Necrosis Factor alfa (TNF-alfa), Interleukin-6 (IL-6), and Interleukin-1 (IL-1) beta (IL-1F2), contributing to neuronal cell death.
Misfolded and aggregated proteins bind to pattern recognition receptors on micro - and astroglia and trigger an innate immune response , characterized by the release of inflammatory mediators, which contribute to disease progression and severity
Epidemiological and observational studies indicate that users of non-steroidal antiinflammatory drugs (NSAIDs) had a lower risk of developing dementia
The activated astrocytes and microglia produce neuroinflammation in the brain, which serves as a pathology in Alzheimer's Disease (AD)
Acute systemic inflammation events, including various infections, surgical interventions, myocardial infarction, and so on, could boost neuroinflammation and exaggerate cognitive decline
see also:
Alzheimer's disease (AD) & Gut microbiota
Alzheimer’s disease (AD) & Helicobacter pylori infection
Alzheimer's disease (AD) & Immunity
Alzheimer's Disease (AD) & Pathogenicity / Pathology