Alzheimer's Disease: From Immune Homeostasis to Neuroinflammatory Condition

Abstract

Alzheimer's Disease is the most common cause in the world of progressive cognitive decline. Although many modifiable and non-modifiable risk factors have been proposed, in recent years, neuroinflammation has been hypothesized to be an important contributing factor of Alzheimer's Disease pathogenesis. Neuroinflammation can occur through the combined action of the Central Nervous System resident immune cells and adaptive peripheral immune system. In the past years, immunotherapies for neurodegenerative diseases have focused wrongly on targeting protein aggregates Aβ plaques and NFT treatment. The role of both innate and adaptive immune cells has not been fully clarified, but several data suggest that immune system dysregulation plays a key role in neuroinflammation. Recent studies have focused especially on the role of the adaptive immune system and have shown that inflammatory markers are characterized by increased CD4+ Teff cells' activities and reduced circulating CD4+ Treg cells. In this review, we discuss the key role of both innate and adaptive immune systems in the degeneration and regeneration mechanisms in the pathogenesis of Alzheimer's Disease, with a focus on how the crosstalk between these two systems is able to sustain brain homeostasis or shift it to a neurodegenerative condition.

Keywords: Alzheimer’s Disease; CD4+ T cells; homeostasis; immunity; microglia; neurodegeneration; neuroinflammation.

Figure 1

The process of Aβ1–42 formation and plaque deposition. Schematic diagram of the progressive cleavages of the amyloid beta (Aβ) precursor protein (APP) transmembrane domain. Aβ peptide is generated from APP processing via the amyloidogenic pathway, by the β and γ-secretases complex, which produces a peptide called sAPP-β (soluble ectodomain of APP-produced by β secretase) and CTF- β (C-Terminal Fragment by β secretase) fragment and foremost ACID peptide and different lengths of Aβ peptides, including Aβ42, which is more prone to aggregation and plaque formation than Aβ40 and has stronger neurotoxicity and (see the text below for more details).

Figure 2

Role of innate and adaptive immune system in Alzheimer’s disease: (a) The role of innate and adaptive immune systems in CNS homeostasis. In healthy brain tissue, there is a condition characterized by homeostasis and balance between normal neuronal cells; innate immune resident cells, in particular, quiescent microglial and astrocytic cells, which are called “resting microglia” and “resting astrocytes”; and immune peripheral tissue cells, such as quiescent antigen-presenting cells (APCs) that are not activated. In this phase the cerebral environment does not present an inflammation-related activation. (b) The role of innate and adaptive immune systems in Alzheimer’s Disease neuroinflammation condition. Upon several different types of insults, such as genetic, lifestyle, medical, environmental, or psychiatric disorders, healthy neurons become damaged, releasing amyloid plaques and NFTs or self-antigens. These antigens remain in the CNS and stimulate resting microglia, making them an activated phenotype microglia that produce pro-inflammatory mediators such as cytokines, reactive oxygen, and nitrogen species, thus increasing oxidative stress and further increasing the neuronal damage. Misfolded self-proteins are processed and then presented on MHC by APCs to naive to cells in lymph-node tissues. Upon recognition of antigens, T cells differentiate into antigen-specific T-effector (Teff) or T-regulatory (Treg) cells. Teff subsets include Th1, Th2, and Th17. Upon identification of modified self-antigen, activated Teff cells generate neurotoxic and proinflammatory cytokines that drive resting microglia to a reactive state and support a neurotoxic cascade. Th1 and Th17 T cells produce neurotoxic cytokines, such as TNF-α, IL-17, IL-22, and IFN-γ, which are released into brain tissue, promoting an enhanced inflammatory cascade. In response to inflammatory events, Tregs attempt to balance neurotoxic activation through the inhibition of antigen presentation and the production of anti-inflammatory cytokines such Il-10 and TGF-β, with the aim to stop the neuroinflammatory/neurodegenerative condition and promote neuronal homeostasis.