Biolife - Scientific Publisher

Biolife - Scientific Publisher

European Journal of Neurodegenerative Diseases 2020; 9(2) July-December: 44-50


ROLE OF INFLAMMATION IN ALZHEIMER’S DISEASE: AN EMPHASIS ON TREM2 AND CD33

Al. Caraffa *

School of Pharmacy, University of Camerino, Camerino, Italy.

*Correspondence to:
Alessandro Caraffa,
School of Pharmacy,
University of Camerino,
Camerino, Italy.
e-mail: alecaraffa@libero.it

Received: 03 October, 2020
Accepted: 27 December, 2020
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ABSTRACT

Alzheimer’s disease (AD) is the leading cause of dementia globally. It is a progressive and irreversible neurologic disorder that results in personality changes, memory loss, cognitive decline, and death. Hallmarks of the disease include extracellular amyloid-β (Aβ) plaque deposition, the accumulation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau, and neuroinflammation. Aβ plaque deposition is believed to be central to the pathogenesis of AD. Activation of microglia , innate immune cells of the central nervous system, can have both beneficial and harmful consequences, as they are able to aid in Aβ plaque clearance, but also release damaging pro-inflammatory cytokines. Microglial cells are involved with Aβ plaque formations and may play a central role in AD pathogenesis. Diverse gene networks implicating microglia and affecting immune function have been identified, including microglial receptors triggering receptor expressed on myeloid cells 2 (TREM2) and CD33. Both are considerable risk factors for the development of late onset AD and in this paper we summarize their role, and that of microglia, in the inflammation occuring in AD.

KEYWORDS: Alzheimer’s disease, inflammation, immunity, TREM2, CD33, microglia, neurology, neurodegenerative

  

INTRODUCTION

 

Alzheimer’s disease (AD) is a progressive neurologic disorder and the leading cause of dementia worldwide (1). Most cases are late onset, usually occurring after the age of 65 (2). It is characterized by extracellular amyloid-β (Ab) plaque deposition and the accumulation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau. Symptoms include memory loss, changes in personality and behavior, progressive cognitive decline, and eventually, death. Genetic changes can cause AD to an extent.

AD is complex, but different theories exist to explain the mechanisms involved. The most predominant is the Ab cascade hypothesis, focusing on Ab accumulation as the fundamental element in AD development (3). It theorizes that Aß groups to form plaques on the outside of brain neurons, followed by inflammation and NFTs of tau protein, eventually leading to neuronal death, which then results in neurodegeneration. Evidence has suggested that the inability to clear Ab is central to AD pathogenesis, rather than the overproduction of Ab (4).

Neuroinflammation is another hallmark of AD, with elevated expression of inflammatory mediators, and microglia and astrocytes showing changes in morphology, activation, and distribution (5) (6). Microglia are innate immune cells resident in the central nervous system (CNS), responsible for immune surveillance and mediation. They are important for tissue repair and damage-control, but their response can also be detrimental with the release of pro-inflammatory substances. It is believed that inflammation mediated by microglia plays a central role in the progression of AD, but the process is complex and the exact mechanisms by which this occurs is still unclear.

CD33 and triggering receptor expressed on myeloid cells 2 (TREM2) are microglial receptors that regulate inflammation in AD and are associated risk factors. In this paper we summarize the pathogenesis of late onset AD with a focus on the role of microglia in inflammation and the involvement of CD33 and TREM2.

 

Microglial cells

In the brain, microglia have functions similar to macrophages, providing immune surveillance and tissue maintenance. Microglial cells and Ab formation are linked. Microglia protect the CNS by helping to clear Ab plaque formations, yet fibrillar Ab can activate microglia, leading to the release of inflammatory mediators, such as pro-inflammatory cytokines, that can be damaging to the CNS (7).

Microglia are plastic, with the ability to change phenotype in response to stimuli, and interact with neurons to mediate the immune environment (8). They show branching dynamics, the capability to expand and retract into neighboring tissue, which allows for continuous immune surveillance and rapid convergence to an injury site (9). This includes the response to Ab plaque that occurs with AD.

Ab plaque formation can activate microglia to an inflammatory phenotype, as seen in animal models (10, 11). Microglia congregate to Ab deposits, mostly converging at the sites of densely concentrated plaques, with fewer observed in unconcentrated surrounding areas (12, 13). Microglia are attracted to plaque, congregating around formations, and increasing and growing in size over time (14-16).

Surface cell receptor and toll-like receptor (TLR)-detection of intracellular proteins and damage-associated molecular patterns (DAMP) molecules initiate the innate immune response to injury. Interestingly, increased expression of CD14 (17), TLR2, and TLR4 (18) by microglia has been seen in the AD brain (19).

In the AD brain, deposition of fibrillar forms of Aβ occurs, activating microglia through a cell surface receptor complex that includes the B-class scavenger receptor CD36, the integrin-associated protein/CD47, and the α6β1-integrin (20). This leads to signaling cascades, and the defensive reaction of activated microglia includes the production of free radicals and the release of pro-inflammatory cytokines that can contribute to CNS injury. The inflammation that occurs is thought to be integral in the progression of the disease. In fact, microglial activation in AD brains has been associated with elevated levels of cytokines and chemokines, such as interferon γ (IFNγ), tumor necrosis factor (TNF), interleukin 1β (IL-1β), interleukin 6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) (21-24).

In their role as principle immune effectors, microglia participate in phagocytosis, removing and clearing targets such as pathogens, apoptotic cells, and cellular debris. Microglia can internalize fibrillar forms of Aβ, but degradation and complete clearance is not always effective (25-27). Diverse studies have shown that inflammation may negatively interfere with the ability of microglial cells to clear Aβ plaques (28-30).

Additionally, microglia cell surface receptors are important for Aβ recognition and subsequent response (31). Microglia require the triggering receptor TREM2 for the phagocytosis of certain substrates, including Aβ (32). TREM2-deficient microglia were seen to remain inactivated and not congregate around Aβ plaques (33, 34) (Fig. 1).

 

Fig. 1. Amyloid-β (Aß) groups to form plaques on the outside of brain neurons, causing neuronal damage. Ab plaque deposition activates microglial cells, which congregate to sites of Ab plaque formation and release free radicals and pro-inflammatory cytokines, leading to inflammation and subsequent neuronal damage.

 

Genetic risk factors

Heritability for late onset AD is high, does not differ by sex, and is estimated to be between 58-79% in twin studies (35). Apolipoprotein E ε4 (APOE ε4) was the first confirmed genetic risk factor (36), until recently when many different genes have been identified to be associated with the development of AD, numerous of which are also associated with inflammation and microglia (37). Some of these gene networks that are closely tied to the immune system, such as CR1, SPI1, the MS4As, TREM2, ABCA7, CD33, and INPP5D, are expressed by microglia (37). This supports the role that neuroinflammation plays in the development of AD.

Microglial receptors TREM2 and CD33, which are involved in immune function activation and are associated with one another, are of particular interest in AD. CD33 is one of the top-ranked genes for risk of AD and is exclusively expressed in microglia. Rare variants of TREM2 are a considerable risk factor and can increase the risk of developing AD by 2-4 times (5).

 

CD33

CD33 is a transmembrane myeloid cell receptor that is expressed in microglia and macrophages in the brain, with the ability to inhibit immune cell functions. In genome-wide association studies, CD33 has been identified as one of the greatest risk factors for AD (38-40), with two variants posing the highest risk, rs3865444 and rs12459419 (41,42).

Studies have suggested that CD33 is involved in diverse immune functions, including cell adhesion processes, endocytosis, immune cell growth, TLR4 signaling, and can inhibit the release of cytokines (43-45).

It is believed that its expression regulates the activation of microglia and interferes with the clearance of Aβ by inhibition, with Aβ plaque formation resulting in turn (46). CD33 is increased in the brain with AD, correlated with disease severity as well as extent of Aβ plaque formation (47). The T allele of single-nucleotide polymorphism (SNP) rs3865444 has been associated with decreased CD33 levels and Aβ plaque burden in the brain (45), and the C allele was associated with increased CD33 levels and Aβ plaque burden (48).

Evidence shows that CD33 may inhibit the production of pro-inflammatory cytokines such as IL-1β, TNF, IL-8, and furthermore, increased TNF secretion by immune cells was seen with the downregulation of CD33 (49). Animal studies have also revealed evidence, as mice without CD33 showed greatly reduced Aβ plaque levels (45).

Because CD33 inhibits Aβ clearance, subsequently generating the formation of Aβ plaques, targeting CD33 could be a therapeutic opportunity in AD.  

 

TREM2

TREM2 is a triggering receptor expressed on myeloid cells, and microglia are responsible for TREM2 expression in the CNS, where it is associated with inflammation (5). It can suppress the production of pro-inflammatory cytokines and promote phagocytosis of Aβ plaque by microglia (50,51).

TREM2 expression is increased by the expression of anti-inflammatory molecules, while pro-inflammatory ones, such as TNF and IL-1β, decrease its expression (51,52). Microglial aggregation to Ab plaques causes upregulation of TREM2, which has been reported in animal models and humans (53,54). TREM2 upregulation is also associated with aging (55).

TREM2 binds to Aβ, is involved in microglial activation and degradation of Aβ, and mediates the microglial expression of cytokines (56). TREM2 expression promotes phagocytosis by microglia, which has been seen in studies correlating increased expression with increased phagocytosis (50,57), and decreased phagocytosis with TREM2 loss (58,59). TREM2 moderates microglial functions and binds to Aβ, and mutations of TREM2 in AD reduce Aβ binding (56). TREM2 also modulates inflammation by signaling and has anti-inflammatory effects (50), although some studies seem to show an association with pro-inflammatory effects as well (60,61). Lastly, TREM2 affects the proliferation and survival of myeloid cells, including microglia (59).

TREM2 variants are a significant risk factor for late onset AD. Rs75932628 is a common TREM2 gene variant risk factor. It has been identified in European and North American populations in diverse studies but cannot be confirmed in Chinese communities (62-65).

 

CONCLUSIONS

 

AD is a prevalent and highly complex neurodegenerative disorder. Increasing evidence suggests that inflammation plays a vital role in the development of the pathogenesis of the disease. Aβ plaque deposition is thought to be a fundamental characteristic of AD. The inability to effectively clear Aβ plaque formations is likely the key to disease progression, rather than Aβ overproduction. Microglia and Aβ are closely associated, with formation of Aβ plaques activating microglia and causing microglial congregation. Microglia aid in phagocytosis and clearance of Aβ but can also release harmful pro-inflammatory cytokines.

Heritability is high and diverse genes have been identified that implicate microglia and immune function in the development of AD.  Microglial receptors CD33 and TREM2 are involved in immune function and are two significant risks factors for AD development.

CD33 expression regulates microglial activation and inhibits the clearance of Aβ plaque. TREM2 is expressed by microglia in the CNS, where it suppresses the release of pro-inflammatory cytokines and promotes phagocytosis by microglial cells.

Further research focusing on CD33 and TREM2 is necessary to expand our understanding of their exact functions in AD, which could lead to therapeutic opportunities.

 

Conflict of interest

The author declares that they have no conflict of interest.

 

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