The Role of Immunity in Alzheimer's Disease

Abstract

Based on this, it has been suggested that reducing co-morbidities in the elderly and extending the period of healthy aging will have a significant impact on decreasing the number of individuals with such impairments in 2050, with a knock-on effect of reducing the cost of dementia care.It is widely acknowledged that neuroinflammation is a critical step on the road to dementia. It is produced as a reaction to the ongoing protein deposition and cell loss observed in individuals with cognitive impairment and it has been argued that such inflammatory factors can in turn exacerbate ongoing cellular changes and hasten the progression to severe cognitive decline. This review will detail the role of the innate and adaptive immune system in the progression of AD. Specifically we will cover microglia mediated-neuroinflammation and the contribution of peripheral cells, namely T cells, on the progression to cognitive decline and the potential therapies that are under development to tackle these pathways will be discussed. Alzheimer's DiseaseThe most common cause of cognitive impairment or dementia is AD. This accounts for 60-80% of dementia cases [5] and is characterized by the build-up of two different proteins, amyloid-β (Aβ) and tau, along with cognitive changes. Aβ is cleaved from amyloid precursor protein (APP) and these monomers aggregate into oligomers and fibrils, ultimately forming Aβ-containing plaques that are 200-650 μm 2 in size. [6] Aβ can also undergo posttranslational modifications such as phosphorylation and nitration, which accelerate this process. [7,8] Tau is a protein found in neurons that is involved in microtubule stabilization, however in AD (and other Frontotemporal dementias -FTDs) tau becomes hyperphosphorylated and accumulates forming neurofibrillary tangles (NFTs). These deposits vary considerably in size from 10 to 500 μm 2 . [9] The severity of pathological changes (particularly the NFTs) correlate with neuronal loss and the increasing cognitive decline in those with AD. [10][11][12] The observed cognitive impairment in AD differs significantly across disease stages, and ranges from mild cognitive impairment (MCI), which can progress to moderate and then severe dementia. Indeed 68-80% of those who receive an initial diagnosis of MCI go on to develop AD within 6 years. [13][14][15] MCI is the first stage of cognitive decline and features initial With the increase in the aging population, age-related conditions such as dementia and Alzheimer's disease will become ever more prevalent in society. As there is no cure for dementia and extremely limited therapeutic options, researchers are examining the mechanisms that contribute to the progression of cognitive decline in hopes of developing better therapies and even an effective, long-lasting treatment for this devastating condition. This review will provide an updated perspective on the role of immunity in triggering the changes that lead to the development of dementia. It will detail the latest findings on Aβ-and tau-induced microglial activation, i...

The Role of Microglia in Alzheimer’s Disease From the Perspective of Immune Inflammation and Iron Metabolism

“…The human body can defend itself against pathogenic invasion as well as endogenous damage through adaptive and innate immune systems (McManus, 2022). The initiation of the immune system is largely dependent on various macrophages (including microglia), which express pattern recognition receptors (PRRs).…”

“…The initiation of the immune system is largely dependent on various macrophages (including microglia), which express pattern recognition receptors (PRRs). Activation of these PRRs triggers a rapid signal transduction pathway that releases cytokines and chemokines, affecting cellular function (McManus, 2022). Neuroinflammation can be defined as the response of the CNS to exogenous and/or endogenous factors that interfere with normal cellular homeostasis (Maccioni et al, 2018).…”

Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease

“…Although most T cells in the AD brain are not fully developed effectors, the cytokines they release may influence the pathogenic developments in AD [ 9 , 12 ]. Although T cell proliferation in the AD brain is low, once within the brain, T cells interact with microglia or astrocytes functioning as antigen-presenting cells (APC) to perform their effector tasks [ 13 , 14 ]. It is clear that microglia play a significant role in AD development.…”

“…Early Aβ and tau deposition results in microglial activation, NLRP3 inflammasome assembly, and cytokine and protein release. However, because the original triggers, such as Aβ and tau, are not eliminated, continuous microglial activation exacerbates AD pathogenesis and results in greater protein buildup and neuroinflammation [ 14 , 15 , 16 ].…”

Engineered macrophage-biomimetic versatile nanoantidotes for inflammation-targeted therapy against Alzheimer's disease by neurotoxin neutralization and immune recognition suppression

“…As primary resident immune cells in the central nervous system (CNS), microglia maintain brain microenvironment homeostasis by triggering innate immune responses [ 3 ]. In AD brain, excessive neurotoxins such as lipopolysaccharide (LPS) and amyloid-beta (Aβ) aggregates bind to pattern recognition receptors (PRRs) on microglial membranes as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), resulting in sustained microglial activation and long-term release of inflammatory mediators, ultimately leading to synaptic damage and neuronal dysfunction [ 4 , 5 ]. It is worth noting that the deleterious inflammatory phenotype of microglia during AD progression depends on the specific immune recognition of neurotoxins by PRRs, which is increasingly recognized as a trigger for the onset of microglia-mediated pro-inflammatory cascade.…”