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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 37  |  Issue : 4  |  Page : 155-163

Neuroinflammation in Alzheimer's disease continuum


1 Department of Neurology, Faculty of Medicine, TOBB ETU, Ankara, Turkey
2 Institute of Neurological Sciences and Psychiatry; Department of Neurology, Faculty of Medicine, Hacettepe University; Neuroscience and Neurotechnology Center of Excellence (NÖROM), Ankara, Turkey

Date of Submission16-Oct-2020
Date of Acceptance24-Oct-2020
Date of Web Publication29-Dec-2020

Correspondence Address:
Aslihan Taskiran-Sag
Department of Neurology, Faculty of Medicine, TOBB ETU, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/nsn.nsn_190_20

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  Abstract 


Aging population brings an ever-increasing global burden of dementia, and Alzheimer's disease (AD) is the most frequent type worldwide. Many years of research have introduced characteristic cerebral histopathological and molecular changes in this disease. However, all attempts to establish an effective treatment have failed. In this review, we aim to address the basic evidence regarding the role of inflammatory mediators in AD and their link to the other pathogenetic pathways. Novel findings based on advanced biotechnology and bioinformatics are covered briefly, as well.

Keywords: Alzheimer's, amyloid, disease-associated microglia, inflammation, microglia, TREM2


How to cite this article:
Taskiran-Sag A, Yemişçi M. Neuroinflammation in Alzheimer's disease continuum. Neurol Sci Neurophysiol 2020;37:155-63

How to cite this URL:
Taskiran-Sag A, Yemişçi M. Neuroinflammation in Alzheimer's disease continuum. Neurol Sci Neurophysiol [serial online] 2020 [cited 2021 Sep 22];37:155-63. Available from: http://www.nsnjournal.org/text.asp?2020/37/4/155/305384




  Introduction Top


Alzheimer's disease (AD) is most common among dementias all over the world.[1] Its main features are memory impairment, irreversible progressive cognitive decline, and neuronal loss. It is the most frequent and debilitating neurodegenerative disease. However, the direct cause is still unknown except for the genetic cases. Aging is the greatest risk factor so far. Prevalence increases with increasing life expectancy all over the world, so does the clinical and financial burden associated with it.[2]

There is a preclinical stage of the disease, at which patients are yet symptom free. However, toxic changes already take place in the brain during this stage. These changes may actually begin a decade or more before the symptoms appear. Abnormal depositions of proteins form amyloid plaques and tau tangles throughout the brain. These constitute the two core pathologies of AD: Beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs). Briefly, Aβ pathology results from the improper cleavage of amyloid precursor protein (APP).[3] The exact function of APP is still unknown, however it is a transmembrane protein that is supposed to have roles in neuronal development, neurite growth, and axonal transport.[4],[5] APP may be processed by three secretases: alpha, beta, and gamma. When beta and gamma secretases instead of alpha catalyze its cleavage, this results in the formation of Aβ monomers that aggregate and form oligomeric Aβ. They further aggregate into Aβ fibrils and eventually form plaques.[6] As Aβ plaques start to accumulate even 10 years before the onset of overt symptoms, the accurate role of Aβ in AD pathophysiology is still questionable.[7] NFTs constitute the second core pathology. They are aggregates of a microtubule-associated protein, tau in hyperphosphorylated form. Normally, tau stabilizes microtubule structures in the cells, and the microtubule function is regulated by phosphorylation (removal of tau) and dephosphorylation (binding of tau) during intracellular processes. In AD, tau is hyperphosphorylated at multiple sites and, thus, is removed from microtubules, ending up with their collapse; this eventually leads to disruption of multiple neuronal functions and neuronal morphology. In addition, hyperphosphorylated tau forms intracellular aggregates, which are called NFTs.[8],[9],[10],[11],[12] These also cause loss of cellular function and apoptosis.[13] Aβ and NFTs do not develop in parallel in the brain. Aβ plaques are believed to be a temporally “upstream” feature. This is what Dr. John Hardy and Dr. Higgins called amyloid cascade hypothesis in 1992.[14] They hypothesized that formation of Aβ deposits is the leading element in pathogenesis and it triggers tau pathology, and all the other histopathological processes.[14] An additional observation highlighting the role of Aβ in this process is the strong association between AD genetics and Aβ plaque formation [Figure 1]. All the genetic features which are high risk for AD (i.e., apolipoprotein E [APOE] ε4 allele, trisomy 21, APP mutation, and presenilin mutations) have been linked with increased Aβ deposition. This is of importance because the genetic factors constitute approximately 70% of an individual's risk for AD.[15],[16],[17],[18]
Figure 1:Conventional theories for Alzheimer's disease pathogenesis. Right: Amyloid cascade hypothesis. Left: Vascular hypothesis

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However; all ventures to develop drugs targeting Aβ to treat AD have ended in failure.[19] Some of these studies have been successful in animal models and some were effective in decreasing amyloid burden in the brain, but useless in terms of clinical efficacy. There are ongoing trials evaluating anti-amyloid treatments at prodromal and preclinical stages. Clinical evidence regarding tau-targeting therapies have been limited, so far.[20]

As of today, there is no cure for AD. We have five drugs that can be used in the treatment of AD. They are all symptomatic remedies; four of them are cholinesterase inhibitors and the other one is N-methyl-D-aspartate receptor antagonist. These drugs were proven to be safe and effective enough to be used in the daily treatment of AD,[21],[22],[23] and they temporarily improve cognitive symptoms and global status. They do not treat the upstream, underlying cause of AD. Even it is shown that they slow the rate of decline, their clinical effect is modest, and real-world effect on all-cause mortality of AD patients is variable.[24],[25],[26],[27],[28],[29],[30] Hence, there seems to be some gaps in understanding AD pathogenesis.

Numerous autopsy findings worldwide revealed that people who did not have clinical AD actually had AD-like neuropathological changes in their brain or vice versa . This discordance between cognitive status and pathological findings pointed out to the controversial aspects of neuropathological approach, leading to the emergence of new hypotheses. One of them was the vascular hypothesis. Many of the primary risk factors for AD are related to the integrity of cerebrovascular structure and function. Moreover, cortical cerebral blood flow was found to be abnormal both in AD patients and in transgenic amyloid mice, early in disease development.[31],[32] Now, many scientists emphasize brain hypoperfusion and oligemia as the initiator of the pathological events.[33],[34],[35],[36],[37],[38] They claim that the capillary changes and neurovascular dysfunction are in the upstream of AD pathogenesis and lead to neuroglial energy crisis, which in turn affects cognitive function. With the accumulation of neurodegenerative changes, neurons are progressively lost and dementia settles.


  Another Core Pathology Emerging: Neuroinflammation Top


The idea behind the inflammatory theory of AD is basically the imbalance between pro- and anti-inflammatory signaling within the brain tissue. This results in low-grade but persistent neuroinflammation, which is not exclusive to AD. There are plenty of studies indicating elevated markers of inflammation in other neurodegenerative diseases as well. Making a distinction whether it is a response to primary pathology and neuronal loss, or it is another mechanism that pursues the pathogenesis, has been challenging to many researchers in this area.

The first hints for an ongoing inflammation in addition to amyloid plaques and tangles in AD brains were found in the 1980s, when researchers discovered that immunoglobulins and complement factors were present in senile plaques; besides, the cellular expression of immune system-associated proteins in AD patients' brains was more than that of controls.[39],[40] Few years later, immunohistochemical staining of interleukin (IL)-1 and S100 in brain sections of AD or Down syndrome patients showed thirty times more positivity compared to age-matched controls and, importantly, labeling was prominent not in neurons, but in microglia.[41] These observations were corroborated by many postmortem studies reporting the presence of a sustained inflammatory response in AD brains.[42],[43],[44],[45] It was also suggested that activation of microglia with IL-1 expression is necessary for plaque evolution, changing the diffuse amyloid deposits into neuritic plaques, which are characteristic and diagnostic of AD.[46] Complement factors, tumor necrosis factor (TNF)-alpha, IL-1β, and IL-6 have been linked to neurodegeneration, amyloid, and tau pathology in both human and experimental studies; furthermore, serum, cerebrospinal fluid, or tissue levels of these pro-inflammatory cytokines were found to be elevated in AD.[47],[48],[49],[50],[51],[52],[53] The ability of Aβ to induce IL-6 release from glial cells[54] and the fact that Aβ is capable of activating complement system by itself[55] provided strong evidence to link neuroinflammation to AD pathology.[56] Membrane attack complex structures were identified on dystrophic neurites in AD brains.[57] Imaging data were also in line with increased inflammatory response in AD.[58],[59]

In the 1990s, some epidemiological observations suggested that long-term nonsteroid anti-inflammatory drug (NSAID) users demonstrated a 50% decrease in the risk for developing AD.[60],[61] Many animal studies followed and established that adequate doses of NSAIDs reduce both neuroinflammation and the amyloid burden in different transgenic mouse models of AD.[62] As these data were very promising, various prospective human trials were initiated. However, a meta-analysis of randomized controlled clinical trials revealed no convincing evidence of benefit as a treatment despite their success in the preclinical models.[63] Still, it implied significant points to the researchers on the role of neuroinflammation on AD pathogenesis.


  Where Does Neuroinflammation Stand in Alzheimer's Disease Pathogenesis? Top


According to many studies, the obvious increase in inflammation-related elements in AD brains was damaging.[49],[64] Small vessels of brain were thought to be injured by oxidative-induced inflammation,[37] meaning that vascular hypothesis of AD may also be propagated by or at least linked to neuroinflammation. The main inflammatory pathway in neuroinflammation of AD appears to be innate immune response,[65] with microglia emerging as the primary cellular actor in it.[7] Aβ can induce microglial activation through pattern recognition receptors and then microglia release numerous cytokines such as TNF-α, IL-1β, and IL-6. TNF-α is known to upregulate β-secretase production and increase γ-secretase activity.[66],[67] IL-1β is a master regulatory cytokine with pro-inflammatory effects, which is considered crucial also for Aβ plaque deposition.[49] IL-6 enhances APP expression, as well as the activity of a kinase CDK5 , which hyperphosphorylates tau.[68],[69] Aβ oligomers directly interact and activate NLRP3 inflammasome.[70] Recently, NLRP3 inflammasome activation was proposed to drive tau hyperphosphorylation and aggregation, being a possible link between amyloid pathology and tau pathology [Figure 2].[71]
Figure 2: Clues and possible interactions between amyloid β, tau pathology, and innate immunity. Amyloid β is capable of activating complement system and microglia, inducing release of many cytokines and activating NLRP3 inflammasome. Soluble amyloid β oligomers may bind to TLR4, TLR6, and CD36 on microglial cell surface and cause their activation. Microglia release pro-inflammatory cytokines. These cytokines are also capable of inducing amyloid protein expression and CDK 5 activity, thus further increasing amyloid and tau pathology. NLRP3 inflammasome increases tau phosphorylation and aggregation. Notice all the elements being part of innate immunity

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As a matter of fact, microglia do engulf Aβ plaques, so in the early disease course, innate immune response serves as a means to clear up the amyloid deposits within the brain.[48],[72] Transforming growth factor -β, C3, and IL-1β appeared to be especially important in promoting microglia-mediated clearance of plaques.[73],[74] However, when this activation becomes chronic, reactive microgliosis ensues.[75] Sustained release of pro-inflammatory cytokines and some other toxic products (reactive oxygen species, nitric oxide, etc.) aggravates tissue damage and further accumulation of Aβ.[76] Chronic activation of microglia also decreases the efficiency to engulf and clear Aβ plaques.[77] Substantially, these cells continue to maintain immune activation while they lose their early beneficial effects in the pathogenesis.[7]

The interaction between IL-1β and Aβ is bidirectional. High levels of IL-1β induce APP production and increase Aβ load; besides, Aβ stimulates IL-1β production.[47],[78] The production of other cytokines such as IL-6 is induced, which in turn has been associated with tau-hyperphosphorylation and increased APP production.[68],[69] Neuroinflammation appears to aggravate the disease by exacerbating Aβ and tau pathologies.

The primary trigger for microglial activation is thought to be the presence of Aβ. Soluble Aβ oligomers and fibrils bind with CD36, TLR4, and TLR6 on the cell surface of microglia.[79],[80] Activated microglia migrate to the plaques, and phagocytose Aβ.[81],[82] However, ongoing production of Aβ peptides and positive feedback loops that exist between APP and inflammation lead to enlargement of these microglia and insufficiency of their phagocytic capacity after prolonged periods.[65],[75],[83] In addition to that, aging microglia start to express less Aβ-degrading proteolytic enzymes (insulysin, neprilysin, and MMP9) and more pro-inflammatory cytokines in transgenic AD mice, supporting an important link to the major AD risk factor, aging.[75] Considering the plasticity of microglial phenotype, many scientists tried to trigger microglia to clear plaques, via Fc receptor-mediated phagocytosis and ensuing peptide degradation, and they succeeded in promoting the clearance of preexisting amyloid deposits. This was the basis of what is called “amyloid immunotherapy.” However, clinical trials raised many safety and efficacy concerns.[84],[85]

Similarly, researchers utilized statins to degrade extracellular Aβ peptides by microglia. These molecules are capable of stimulating exosome-associated insulin-degrading enzyme secretion and enhance extracellular clearance of Aβ.[86] However, no clinically significant changes were detected in randomized human trials so far.[87],[88],[89]

An important discovery regarding the role of neuroinflammation in AD came from triggering receptor expressed on myeloid cells-2 (TREM2) studies. TREM2 is a surface receptor required for microglial responses. Its mutations were known to be associated with a rare but severe form of degenerative disease (Nasu–Hakola disease).[90] Two epidemiological studies regarding TREM2 variants put forth an association with the risk of AD.[91],[92] Variant rs75932628 brought a significantly increased risk to develop AD. Its mechanistic role in AD pathophysiology has been investigated since then, and altered microglial response, decrease in the number and size of plaque associated-microglia, alterations in inflammatory cytokines and astrocytosis, and exacerbation of tau pathology were some of the changes to be reported.[93],[94],[95],[96],[97],[98] There were also some divergent findings implying that its deficiency could be neuroprotective. Therefore, TREM2 appears to have possible disease stage-specific contributions to AD pathogenesis.[99] In parallel to that, some researchers found serum TREM2 levels being higher in AD patients than that in controls but highest in mild cognitive impairment patients, especially if they were progressing to AD and if they were ApoEε4 carriers.[100] The interactions between TREM2 and ApoEε4 molecules may be facilitatory in the pathogenesis during the preclinical phase of AD. Therefore, TREM2 may be suggested as an early serological biomarker for the development of AD.[100] In 2017, Colonna et al . showed that TREM2 risk variants in AD patients and TREM2 deficiency in AD mice were related to increased autophagy through defective mammalian target of rapamycin (mTOR) signaling. They unraveled its linkage to the biosynthetic machinery and the cellular energy metabolism of the microglia.[101] This was a new perspective in AD research, still looking for a potential therapeutic strategy.


  Other Possible Therapeutic Targets Top


Recurring disappointment in the clinical trials for AD therapy necessitates extending our approach beyond conventional theories. While the investigations on the role of TREM2 were going on, some researchers focused on the local cerebral effects of systemic immune response.[102] The main idea was that systemic immune suppression might depress the ability to establish defensive, cell-mediated immune responses necessary for brain repair. Similar to cancer immunotherapy, immune checkpoint inhibition was applied systemically through programmed death-1 (PD-1) pathway to the mouse models of AD. It released an interferon γ-dependent systemic immune reaction, which was followed by the recruitment of monocyte-derived macrophages to the brain. In mice with existing amyloid pathology, this immunological response led to the clearance of Aβ plaques and improved cognition.[102],[103] The success of this approach yet fails to be replicated by other laboratories.[104],[105],[106]

Recent advances in biotechnology and bioinformatics made it possible to map all the immune cell populations in transgenic AD mouse brains.[107] This led to the identification of a novel microglia subpopulation, named disease-associated microglia (DAM). They express CD11c, are localized near amyloid plaques, and conserved in both mouse and human species.[107],[108] Time-related changes in the expression profile of microglia and activation[109] are now shown to include a transition from homeostatic microglia toward DAM population as a function of disease progression.[107] DAM cells exhibit enhanced phagocytic activity [Figure 3].[110] This new subtype of microglia associated with restricting neurodegeneration obviously will have important implications for the treatment of Alzheimer's and related diseases.
Figure 3: The role of microglia depends on time and the disease stage. Activated microglia migrate to and engulf amyloid β to clear plaques. Prolonged activation (due to ongoing production of amyloid β) results in enlargement of microglia and altered microglial response. Phagocytosis becomes less efficient, amyloid β-degrading proteolytic enzymes (insulysin, neprilysin, and MMP9) are expressed less, and pro-inflammatory cytokines increase. Consequently, plaque clearance becomes less efficient, while neuroinflammation becomes sustained. This, in turn, leads to some functional and structural changes, some toxic products (reactive oxygen species, etc.), and ultimately degeneration.[65] TREM2, which is a cell surface receptor, is required for proper microglial functioning. Some TREM2 variants are associated with altered microglial response, decrease in the number and size of plaque-associated microglia, changes in inflammatory cytokines, etc. Time-related changes in activation and expression profile of microglia are now evident. Homeostatic microglia transition as a function of disease progression. Disease-associated microglia cells exhibit enhanced phagocytic activity.[110] Suppression or insufficiency of disease-associated microglia activity may have implications in neurodegeneration due to Alzheimer's disease, and could be studied for therapeutic potential

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  Conclusions and Future Directions Top


After many years of research, our understanding of central nervous system as an immune-privileged organ has changed greatly because many elements of the immune system have varying roles in neurodegenerative disorders. Innate immunity has been repeatedly shown to participate in AD pathogenesis, with microglia being the principal actors as they are directly activated by Aβ and release numerous pro-inflammatory elements, which further increase amyloid burden and tau aggregation. Increasing evidence support a role of neuroinflammation linking the core pathologies. Technological advances unravel new molecules, cell populations, and functional phenotypes of immune cells that seem to have important implications in Alzheimer's brains. Neuroinflammation continues to be an unreached but vivid therapeutic target in AD.

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Conflicts of interest

There are no conflicts of interest.



 
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