Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aβ) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aβ accumulation and neuronal loss are not completely clear. Importantly, the blood–brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD.

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

“…The coordinated action of glial cells has been referred to as a "symphony" in the CNS [42]. Both activated microglia and astrocytes participate in the neuroinflammation process [43] (Figure 2).…”

“…This review focuses only on the role of the main cytokines as well as their importance in NDDs. According to very recent literature data, the inflammation cascade plays crucial role in the pathogenesis of AD [43]. One of the main planners of the cascade is the NLRP3 inflammasome.…”

“…Several studies demonstrated that insoluble amyloid aggregates (Aβ, tau, α-syn, huntingtin) can trigger inflammatory processes. Soluble Aβ oligomers can also activate the microglia receptors [43].…”

“…Two signals are necessary for the release of the pro-inflammatory cytokines IL-1β and IL-18. In the first signal, TLR-bound ligands (e.g., LPS, Aβ aggregates) trigger the expression of NLRP3 protein via the nuclear transcription factor NF-κB [43], and then the released NLRP3 monomers may form oligomers (Figure 3). The second signal arises if Aβ binds to the triggering receptor expressed on myeloid cells 2 (TREM2) protein [54] (e.g., if decreased lysosomal degradation results in high Aβ level).…”

Neuroinflammation as a Potential Therapeutic Target in Alzheimer’s Disease

“…It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases and activation of the peroxisome proliferator-activated receptor γ, and some can inhibit BACE1 gene transcription. 66 …”