• Users Online: 320
  • Print this page
  • Email this page

 Table of Contents  
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
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_190_20

Rights and Permissions

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 2023 May 29];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

Click here to view

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

Click here to view

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

Click here to view

  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.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Prince MJ, Wimo A, Guerchet MM, Ali GC, Wu Y-T, Prina M. World Alzheimer Report 2015 - The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. London: Alzheimer's Disease International, 2015. p. 84.  Back to cited text no. 1
Gustavsson A, Svensson M, Jacobi F, Allgulander C, Alonso J, Beghi E, et al . Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:718-79.  Back to cited text no. 2
Anderson JP, Chen Y, Kim KS, Robakis NK. An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequence. J Neurochem 1992;59:2328-31.  Back to cited text no. 3
Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al . The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987;325:733-6.  Back to cited text no. 4
O'Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 2011;34:185-204.  Back to cited text no. 5
Selkoe DJ. Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci 1994;17:489-517.  Back to cited text no. 6
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y) 2018;4:575-90.  Back to cited text no. 7
Iqbal K, Grundke-Iqbal I, Zaidi T, Merz PA, Wen GY, Shaikh SS, et al . Defective brain microtubule assembly in Alzheimer's disease. Lancet 1986;2:421-6.  Back to cited text no. 8
Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, et al . Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res 1989;477:90-9.  Back to cited text no. 9
Šimić G, Babić Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, et al . Tau protein hyperphosphorylation and aggregation in Alzheimer's disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 2016;6:6.  Back to cited text no. 10
Lippens G, Sillen A, Landrieu I, Amniai L, Sibille N, Barbier P, et al . Tau aggregation in Alzheimer's disease: What role for phosphorylation? Prion 2007;1:21-5.  Back to cited text no. 11
Braak H, de Vos RA, Jansen EN, Bratzke H, Braak E. Neuropathological hallmarks of Alzheimer's and Parkinson's diseases. Prog Brain Res 1998;117:267-85.  Back to cited text no. 12
Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: A promising therapeutic target for Alzheimer disease. Curr Med Chem 2008;15:2321-8.  Back to cited text no. 13
Hardy JA, Higgins GA. Alzheimer's disease: The amyloid cascade hypothesis. Science 1992;256:184-5.  Back to cited text no. 14
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al . Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol 2012;71:362-81.  Back to cited text no. 15
Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: A genetic perspective. Cell 2005;120:545-55.  Back to cited text no. 16
Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: Back to the future. Neuron 2010;68:270-81.  Back to cited text no. 17
Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al . Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006;63:168-74.  Back to cited text no. 18
Delrieu J, Ousset PJ, Voisin T, Vellas B. Amyloid beta peptide immunotherapy in Alzheimer disease. Rev Neurol (Paris) 2014;170:739-48.  Back to cited text no. 19
Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 2018;14:399-415.  Back to cited text no. 20
Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al . Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer's disease: A rapid and systematic review. Health Technol Assess 2001;5:1-37.  Back to cited text no. 21
Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006;(1):CD005593.  Back to cited text no. 22
Tricco AC, Ashoor HM, Soobiah C, Rios P, Veroniki AA, Hamid JS, et al . Comparative effectiveness and safety of cognitive enhancers for treating Alzheimer's disease: Systematic review and network metaanalysis. J Am Geriatr Soc 2018;66:170-8.  Back to cited text no. 23
Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL, Liao T, et al . Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer's disease. Dement Geriatr Cogn Disord 2001;12:295-300.  Back to cited text no. 24
Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. The cognitive benefits of galantamine are sustained for at least 36 months: A long-term extension trial. Arch Neurol 2004;61:252-6.  Back to cited text no. 25
Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS. Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res Ther 2009;1:7.  Back to cited text no. 26
Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, et al . Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600-7.  Back to cited text no. 27
Zhu CW, Livote EE, Scarmeas N, Albert M, Brandt J, Blacker D, et al . Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer's disease. Alzheimers Dement 2013;9:733-40.  Back to cited text no. 28
Bhattacharjee S, Patanwala AE, Lo-Ciganic WH, Malone DC, Lee JK, Knapp SM, et al . Alzheimer's disease medication and risk of all-cause mortality and all-cause hospitalization: A retrospective cohort study. Alzheimers Dement (N Y) 2019;5:294-302.  Back to cited text no. 29
Rountree SD, Atri A, Lopez OL, Doody RS. Effectiveness of antidementia drugs in delaying Alzheimer's disease progression. Alzheimers Dement 2013;9:338-45.  Back to cited text no. 30
Nielsen RB, Egefjord L, Angleys H, Mouridsen K, Gejl M, Møller A, et al . Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease. Alzheimers Dement 2017;13:1143-53.  Back to cited text no. 31
Gutierrez-Jimenez E, Angleys H, Rasmussen PM, West MJ, Catalini L, Iversen NK, et al . Disturbances in the control of capillary flow in an aged APP(swe)/PS1DeltaE9 model of Alzheimer's disease. Neurobiol Aging 2018;62:82-94.  Back to cited text no. 32
de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer's disease? Neurol Res 1993;15:146-53.  Back to cited text no. 33
Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci 2004;5:347-60.  Back to cited text no. 34
de la Torre JC. The vascular hypothesis of Alzheimer's disease: Bench to bedside and beyond. Neurodegener Dis 2010;7:116-21.  Back to cited text no. 35
Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 2011;12:723-38.  Back to cited text no. 36
Marchesi VT. Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: Implications for early detection and therapy. FASEB J 2011;25:5-13.  Back to cited text no. 37
Østergaard L, Aamand R, Gutiérrez-Jiménez E, Ho YC, Blicher JU, Madsen SM, et al . The capillary dysfunction hypothesis of Alzheimer's disease. Neurobiol Aging 2013;34:1018-31.  Back to cited text no. 38
Eikelenboom P, Stam FC. Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 1982;57:239-42.  Back to cited text no. 39
Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: Relationship to the pathology of Alzheimer's disease. Neurobiol Aging 1988;9:339-49.  Back to cited text no. 40
Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al . Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 1989;86:7611-5.  Back to cited text no. 41
Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, et al . Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: A microarray study. J Neuroinflammation 2012;9:179.  Back to cited text no. 42
Sudduth TL, Schmitt FA, Nelson PT, Wilcock DM. Neuroinflammatory phenotype in early Alzheimer's disease. Neurobiol Aging 2013;34:1051-9.  Back to cited text no. 43
Wilcock DM. Neuroinflammatory phenotypes and their roles in Alzheimer's disease. Neurodegener Dis 2014;13:183-5.  Back to cited text no. 44
Cacabelos R, Alvarez XA, Fernandez-Novoa L, Franco A, Mangues R, Pellicer A, et al . Brain interleukin-1 beta in Alzheimer's disease and vascular dementia. Methods Find Exp Clin Pharmacol 1994;16:141-51.  Back to cited text no. 45
Griffin WS, Sheng JG, Roberts GW, Mrak RE. Interleukin-1 expression in different plaque types in Alzheimer's disease: Significance in plaque evolution. J Neuropathol Exp Neurol 1995;54:276-81.  Back to cited text no. 46
Akama KT, van Eldik LJ. Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J Biol Chem 2000;275:7918-24.  Back to cited text no. 47
Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al . Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci U S A 2002;99:10837-42.  Back to cited text no. 48
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al . Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421.  Back to cited text no. 49
Forlenza OV, Diniz BS, Talib LL, Mendonça VA, Ojopi EB, Gattaz WF, et al . Increased serum IL-1beta level in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord 2009;28:507-12.  Back to cited text no. 50
Dursun E, Gezen-Ak D, Hanağası H, Bilgiç B, Lohmann E, Ertan S, et al . The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease. J Neuroimmunol 2015;283:50-7.  Back to cited text no. 51
Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett 1995;202:17-20.  Back to cited text no. 52
Hampel H, Haslinger A, Scheloske M, Padberg F, Fischer P, Unger J, et al . Pattern of interleukin-6 receptor complex immunoreactivity between cortical regions of rapid autopsy normal and Alzheimer's disease brain. Eur Arch Psychiatry Clin Neurosci 2005;255:269-78.  Back to cited text no. 53
Chong Y. Effect of a carboxy-terminal fragment of the Alzheimer's amyloid precursor protein on expression of proinflammatory cytokines in rat glial cells. Life Sci 1997;61:2323-33.  Back to cited text no. 54
Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, et al . Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 1992;89:10016-20.  Back to cited text no. 55
McGeer PL, Rogers J, McGeer EG. Inflammation, antiinflammatory agents, and Alzheimer's Disease: The last 22 years. J Alzheimers Dis 2016;54:853-7.  Back to cited text no. 56
Itagaki S, Akiyama H, Saito H, McGeer PL. Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer's disease. Brain Res 1994;645:78-84.  Back to cited text no. 57
Zimmer ER, Leuzy A, Benedet Al, Breitner J, Gauthier S, Rosa-Neto P. Tracking neuroinflammation in Alzheimer's disease: The role of positron emission tomography imaging. J Neuroinflammation 2014;11:120.  Back to cited text no. 58
Versijpt JJ, Dumont F, van Laere KJ, Decoo D, Santens P, Audenaert K, et al . Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur Neurol 2003;50:39-47.  Back to cited text no. 59
Breitner JC, Gau BA, Welsh KA, Plassman BL, McDonald WM, Helms MJ, et al . Inverse association of anti-inflammatory treatments and Alzheimer's disease: Initial results of a co-twin control study. Neurology 1994;44:227-32.  Back to cited text no. 60
Rich JB, Rasmusson DX, Folstein MF, Carson KA, Kawas C, Brandt J. Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology 1995;45:51-5.  Back to cited text no. 61
McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiol Aging 2007;28:639-47.  Back to cited text no. 62
Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Garatachea N, et al . Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer's disease: A systematic review and meta-analysis of treatment effect. Drugs Aging 2015;32:139-47.  Back to cited text no. 63
McGeer PL, McGeer EG. Inflammation of the brain in Alzheimer's disease: Implications for therapy. J Leukoc Biol 1999;65:409-15.  Back to cited text no. 64
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al . Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015;14:388-405.  Back to cited text no. 65
Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS. Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem 2004;279:49523-32.  Back to cited text no. 66
Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, et al . Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 2007;170:680-92.  Back to cited text no. 67
Ringheim GE, Szczepanik AM, Petko W, Burgher KL, Zhu SZ, Chao CC. Enhancement of beta-amyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex. Brain Res Mol Brain Res 1998;55:35-44.  Back to cited text no. 68
Quintanilla RA, Orellana DI, González-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004;295:245-57.  Back to cited text no. 69
Nakanishi A, Kaneko N, Takeda H, Sawasaki T, Morikawa S, Zhou W, et al . Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: Identification of an intrinsic NLRP3 ligand in a cell-free system. Inflamm Regen 2018;38:27.  Back to cited text no. 70
Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, et al . NLRP3 inflammasome activation drives tau pathology. Nature 2019;575:669-73.  Back to cited text no. 71
Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, et al . Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo : Evidence against inflammation as a driving force for amyloid deposition. FASEB J 2010;24:548-59.  Back to cited text no. 72
Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, et al . TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 2001;7:612-8.  Back to cited text no. 73
Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O'Banion MK. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 2007;117:1595-604.  Back to cited text no. 74
Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 2008;28:8354-60.  Back to cited text no. 75
Sheng JG, Zhou XQ, Mrak RE, Griffin WS. Progressive neuronal injury associated with amyloid plaque formation in Alzheimer disease. J Neuropathol Exp Neurol 1998;57:714-7.  Back to cited text no. 76
Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, et al . Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 2013;8:e60921.  Back to cited text no. 77
Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, et al . Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci U S A 1989;86:7606-10.  Back to cited text no. 78
Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al . CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010;11:155-61.  Back to cited text no. 79
El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, et al . CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003;197:1657-66.  Back to cited text no. 80
Baik SH, Kang S, Son SM, Mook-Jung I. Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model. Glia 2016;64:2274-90.  Back to cited text no. 81
Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et al . Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 2008;28:4283-92.  Back to cited text no. 82
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al . Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 2010;330:1774.  Back to cited text no. 83
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al . Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916-9.  Back to cited text no. 84
Panza F, Lozupone M, Seripa D, Imbimbo BP. Amyloid-β immunotherapy for Alzheimer disease: Is it now a long shot? Ann Neurol 2019;85:303-15.  Back to cited text no. 85
Tamboli IY, Barth E, Christian L, Siepmann M, Kumar S, Singh S, et al . Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion. J Biol Chem 2010;285:37405-14.  Back to cited text no. 86
Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, et al . Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010;74:956-64.  Back to cited text no. 87
Simons M, Schwärzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, et al . Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 2002;52:346-50.  Back to cited text no. 88
Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, et al . Atorvastatin for the treatment of mild to moderate Alzheimer disease: Preliminary results. Arch Neurol 2005;62:753-7.  Back to cited text no. 89
Kaneko M, Sano K, Nakayama J, Amano N. Nasu-Hakola disease: The first case reported by Nasu and review: The 50th Anniversary of Japanese Society of Neuropathology. Neuropathology 2010;30:463-70.  Back to cited text no. 90
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al . TREM2 variants in Alzheimer's disease. N Engl J Med 2013;368:117-27.  Back to cited text no. 91
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al . Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 2013;368:107-16.  Back to cited text no. 92
Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, et al . Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's Disease. J Neurosci 2017;37:637-47.  Back to cited text no. 93
Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, et al . Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener 2014;9:20.  Back to cited text no. 94
Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al . TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 2016;213:667-75.  Back to cited text no. 95
Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G, et al . TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener 2017;12:74.  Back to cited text no. 96
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al . TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 2016;92:252-64.  Back to cited text no. 97
Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, et al . TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 2015;125:2161-70.  Back to cited text no. 98
Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, et al . TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A 2017;114:11524-9.  Back to cited text no. 99
Casati M, Ferri E, Gussago C, Mazzola P, Abbate C, Bellelli G, et al . Increased expression of TREM2 in peripheral cells from mild cognitive impairment patients who progress into Alzheimer's disease. Eur J Neurol 2018;25:805-10.  Back to cited text no. 100
Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, et al . TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell 2017;170:649-63.e613.  Back to cited text no. 101
Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, et al . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med 2016;22:135-7.  Back to cited text no. 102
Rosenzweig N, Dvir-Szternfeld R, Tsitsou-Kampeli A, Keren-Shaul H, Ben-Yehuda H, Weill-Raynal P, et al . PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun 2019;10:465.  Back to cited text no. 103
Latta-Mahieu M, Elmer B, Bretteville A, Wang Y, Lopez-Grancha M, Goniot P, et al . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-beta burden in several amyloid transgenic mouse models. Glia 2018;66:492-504.  Back to cited text no. 104
Lin Y, Rajamohamedsait HB, Sandusky-Beltran LA, Gamallo-Lana B, Mar A, Sigurdsson EM. Chronic PD-1 checkpoint blockade does not affect cognition or promote tau clearance in a tauopathy mouse model. Front Aging Neurosci 2019;11:377.  Back to cited text no. 105
Obst J, Mancuso R, Simon E, Gomez-Nicola D. PD-1 deficiency is not sufficient to induce myeloid mobilization to the brain or alter the inflammatory profile during chronic neurodegeneration. Brain Behav Immun 2018;73:708-16.  Back to cited text no. 106
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al . A unique microglia type associated with restricting development of Alzheimer's disease. Cell 2017;169:1276-90.e1217.  Back to cited text no. 107
Kamphuis W, Kooijman L, Schetters S, Orre M, Hol EM. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease. Biochim Biophys Acta 2016;1862:1847-60.  Back to cited text no. 108
Landel V, Baranger K, Virard I, Loriod B, Khrestchatisky M, Rivera S, et al . Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer's disease. Mol Neurodegener 2014;9:33.  Back to cited text no. 109
Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-associated microglia: A universal immune sensor of neurodegeneration. Cell 2018;173:1073-81.  Back to cited text no. 110


  [Figure 1], [Figure 2], [Figure 3]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Another Core Pat...
Where Does Neuro...
Other Possible T...
Conclusions and ...
Article Figures

 Article Access Statistics
    PDF Downloaded406    
    Comments [Add]    

Recommend this journal