New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer’s Disease and Its Potential for Therapeutic Intervention

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics solely focus on symptomatic management instead of preventative or curative strategies. The two most widely accepted pathogenic mechanisms of AD include the amyloid and tau hypotheses. However, it is evident that these hypotheses cannot fully explain neuronal degeneration shown in AD. Substantial evidence is growing for the vital role of neuroinflammation in AD pathology. The neuroinflammatory hypothesis provides a new, exciting lead in uncovering the underlying mechanisms contributing to AD. This review aims to highlight new insights into the role of neuroinflammation in the pathogenesis of AD, mainly including the involvement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed on myeloid cells 2 (TREM2) and cGAS-STING as key influencers in augmenting AD development. The inflammasomes related to the pathways of NF-κB, NLRP3, TREM2, and cGAS-STING as biomarkers of the neuroinflammation associated with AD, as well as an overview of novel AD treatments based on these biomarkers as potential drug targets reported in the literature or under clinical trials, are explored.

Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis

“…There is one major challenge that complicates our understanding of the molecular mechanisms of TREM-2 signaling and its acting as pro- [ 39 , 40 , 41 , 42 ] or anti-inflammatory [ 33 , 34 , 35 , 36 , 37 , 38 ] regulator in inflammatory diseases. Despite TREM-2 binding to a set of potential ligands that are distinct from those recognized by TREM-1, an established inflammation amplifier [ 32 ], TREM2 and TREM-1 both signal through the same signaling partner DAP-12 ( Figure 1 B).…”

“…While the detrimental role of TREM-1 in inflammatory diseases, including RA, has been well established in most studies [ 32 ], that of TREM-2 has been largely controversial. Contrarily to TREM-1, that acts as an inflammation amplifier, TREM-2 has been shown to act either as a negative [ 33 , 34 , 35 , 36 , 37 , 38 ] or positive [ 39 , 40 , 41 , 42 ] regulator of inflammation in various inflammatory diseases.…”

Migraine Pharmacological Treatment and Cognitive Impairment: Risks and Benefits

“…Metoprolol [ 129 ] was found to increase inflammation, whereas TPM [ 43 , 44 ], GBP [ 68 ], duloxetine [ 92 ], fluoxetine [ 107 ], cinnarizine [ 156 ], flunarizine, NSAIDs [ 236 ], and candesartan [ 167 , 173 ] either showed antioxidant capacities or favorably modulate the microglia–astrocyte axis. Neuroinflammation plays a pivotal role in AD and migraine pathogenesis [ 262 ] and represents a key therapeutical target.…”

Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca2+ Homeostasis Dysregulation

“…Nevertheless, the huge plethora of different functions exerted by glial cells, combined with the available evidence suggesting the presence of distinct patterns of activation and the lack of a proper knowledge regarding the molecular regulations underlying cellular transitions, delay the development and design of pharmacological approaches targeting these specific glial subtypes [ 57 , 58 ]. This aim could be pursued through different ways, including the specific suppression of glial pro-inflammatory properties and the modulation of phenotypic changes in order to counteract microglial priming and to maintain protective and phagocytic properties for prolonged periods [ 59 ].…”