Immune attack: the role of inflammation in Alzheimer disease

Journal name:
Nature Reviews Neuroscience
Year published:
Published online


The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, including microglia and several cytokines. In addition, as inflammation in AD primarily concerns the innate immune system — unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides — the concept of neuroinflammation in AD may need refinement.

At a glance


  1. Pathological events in Alzheimer disease and microglial priming.
    Figure 1: Pathological events in Alzheimer disease and microglial priming.

    a | The increase in production and/or reduced clearance of amyloid-β (Aβ), which is derived from the β-amyloid precursor protein (APP), is throught to be a central event in Alzheimer disease (AD). Cleavage of APP occurs either in a non-amyloidogenic ('physiological') or in an amyloidogenic ('pathological') fashion; only the latter results in the production of amyloid-β (Aβ). In the non-amyloidogenic pathway, APP is cleaved first by α-secretase and then by γ-secretase, whereas in the amyloidogenic pathway, γ-secretase cleavage of APP is preceded by β-secretase cleavage, releasing Aβ into the extracellular compartment16. The cleavage site used by γ-secretase in the amyloidogenic pathway determines whether the predominant Aβ40 or the more aggregation-prone and neurotoxic Aβ42 species of the peptide is generated. Aβ monomers may then go on to form oligomers or other arrays, depending on mutations in the Aβ coding region of APP and post-translational modifications16, 204. The arrow thickness indicates the likelihood of conversion of Aβ species or arrays. b | The presence of Aβ (as well as other pathological protein deposits, alterations in the CNS, systemic or local inflammation, and mutations in genes encoding innate immune molecules) can 'prime' microglial cells; that is, Aβ makes these cells susceptible to a secondary stimulus and/or promotes their activation. Priming results in various functional microglia phenotypes (indicated by different colours), presumably accompanied with no or only minor morphological alterations and/or no (major) cell-surface marker differences. In AD, Aβ sustains chronic activation of primed microglia (due to the peptide's accumulation), which results in a constant production of inflammatory cytokines and chemokines by these cells; in turn, the cytokines and chemokines maintain activation of the primed cells. This process results in a vicious circle, which ultimately impairs microglia (although this impairment is reversible for some time); moreover, it affects surrounding CNS resident cells (astrocytes, oligodendrocytes and neurons), possibly aggravating tau pathology (denoted by the dashed line and a question mark), and finally causing neurodegeneration and neuron loss. If these processes perpetuate over a prolonged period, it forces microglia into a senescent, 'burn-out'-like (dystrophic) phenotype, which is thought to be irreversible.

  2. Distinguishing neuroinflammation: innate immune-driven versus adaptive immune-driven neuro-inflammation.
    Figure 2: Distinguishing neuroinflammation: innate immune-driven versus adaptive immune-driven neuro-inflammation.

    Neuroinflammation in various CNS disorders can be differentiated by the nature of inflammation; that is, diseases may be classified according to if CNS-resident and/or potentially blood-derived innate immune cells are the major pathogenic component (as in neurodegenerative diseases such as Alzheimer disease) (a), or if predominantly adaptive immune cells (B and T lymphocytes) drive the pathological process (as seen in encephalitides or multiple sclerosis (MS)) (b). The main contribution — apart from astrocytes — of the innate immune system in neurodegenerative diseases occurs within the CNS through resident microglia and perivascular macrophages, whereas the involvement of other blood-derived myeloid cells such as dendritic cells and monocytes appear to have no major impact on the course of neurodegeneration. Whether — and if so, to what extent — monocytes are recruited from the periphery to the CNS in the course of the disease is not entirely clear (denoted by the dashed arrow and a question mark) (a). Traditionally defined neuroinflammatory diseases such as MS are primarily driven by cells of the adaptive immune system such as T and B lymphocytes; various subtypes of myeloid cells have, however, also important pathogenic implications; blood-derived monocytes represent in fact the most numerous infiltrate into the CNS where they transform into monocyte-derived inflammatory phagocytes (macrophages or dendritic cells) and are thought to mediate much of the tissue damage observed (denoted by the thick arrow). As in neurodegenerative diseases, astrocytes and microglia also react to pathology, although it is not clear whether the type of response is similar to what happens in neurodegeneration (b).

  3. Dynamic, multifaceted interactions with amyloid-[beta] mediate microglial phenotypes in Alzheimer disease.
    Figure 3: Dynamic, multifaceted interactions with amyloid-β mediate microglial phenotypes in Alzheimer disease.

    In both in vitro and in vivo experiments, microglia exhibit receptor-dependent interactions58, 61, 205, 206 with various forms of amyloid-β (Aβ; from monomers to oligomers, protofibrils, fibrils and plaques) as well as non-receptor mediated interactions (particularly with oligomers)81. Aβ species can stimulate changes in microglial function or production of inflammatory mediators through signalling receptors207, by inducing production of such mediators by other cells such as astrocytes208 and through post-phagocytic processes within microglia, including lysosomal injury, which acidifies the cytosol and contributes to activating the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome149. Receptor-mediated interactions between microglia and Aβ monomers do not show evidence for altered microglial function aside from induction of a 'primed' state, typified by heightened responses to subsequent DAMP (damage-associated molecular pattern) or cytokine stimuli. Microglia function, as monitored by motility in response to laser lesion and phagocytic activity of latex beads, is severely impaired in APPPS1 Alzheimer disease (AD) mice75, known to also exhibit oligomeric Aβ209. This functionally compromised state affects the microglial response to downstream Aβ species such as fibrils and plaques, culminating in a morphology and irreversible phenotype that is termed 'dystrophic' — corresponding to a 'burn out' of microglia (see also Fig. 1b). The arrow thickness indicates the likelihood of conversion of Aβ species or arrays.

  4. Proposed A[beta]-dependent CNS specific non-adaptive IL-12 and IL-23 actions in AD.
    Figure 4: Proposed Aβ-dependent CNS specific non-adaptive IL-12 and IL-23 actions in AD.

    a | In healthy brains, microglia do not express detectable levels of interleukin-12 (IL-12) or IL-23, and astrocytes are largely unresponsive to these cytokines. b | In Alzheimer disease (AD), exposure to Aβ leads to expression of both of these cytokines in microglia and reactive astrogliosis is accompanied by the expression of the respective receptors by astrocytes66. It is not clear whether the astroglial expression of IL-12 and IL-23 receptors is mediated by other cytokines or whether Aβ per se can also induce IL-12 and IL-23 receptor expression on astrocytes (denoted by the dashed arrows). This rise in IL-12 and IL-23, and their receptors, leads to exacerbation of AD pathology, including increased deposition of Aβ and ultimately to cognitive impairment, presumably through neuronal damage, whereas inhibition of the IL-12–IL-23 signalling pathway ameloriates pathology. However, what remains to be resolved is whether the IL-12- and IL-23-mediated effects in the CNS are conferred by astrocytes and/or by microglia, and whether IL-12 or rather IL-23 acts as the major player in this context.


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  1. Department of Neuropathology, Charitéplatz 1, Charité - Universitätsmedizin Berlin, D-10117 Berlin, Germany.

    • Frank L. Heppner
  2. Cluster of Excellence, NeuroCure, Charitéplatz 1, D-10117 Berlin, Germany.

    • Frank L. Heppner
  3. Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, USA.

    • Richard M. Ransohoff
  4. Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zrich, Switzerland.

    • Burkhard Becher

Competing interests statement

F.L.H. and B.B. hold a patent application entitled 'Modulators of IL-12 and/or IL-23 for the Prevention or Treatment of Alzheimer's Disease' (PCT/EP2012/050066) and are founding scientists of Myosotis Therapeutics AG, which has exclusive licensing rights from the University of Zurich and the Charité –Universitätsmedizin Berlin. R.M.R. is an employee of Biogen.

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  • Frank L. Heppner

    Frank L. Heppner is full professor of Neuropathology and Chairman of the Department of Neuropathology at the Charité – Universitätsmedizin Berlin, Germany. After his medical training in Lübeck, Hamburg, Berlin, Germany, and London,UK, he became a postdoctoral fellow, then a resident and a senior consultant in neuropathology at the University of Zurich, Switzerland, and Bonn, Germany. By utilizing murine disease models, his research aims to understand the impact of the immune system on the pathogenesis of neurodegenerative diseases, mainly Alzheimer disease. He also has a long-lasting interest in understanding microglia biology in health and disease. Frank L. Heppner's homepage.

  • Richard M. Ransohoff

    Richard M. Ransohoff is Senior Biogen Research Fellow, Neuroimmunology, at Biogen, Cambridge, Massachusetts, USA, and adjunct Professor of Molecular Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (CWRU), Cleveland, Ohio, USA, where he received his M.D. and performed postdoctoral research. After residencies in internal medicine (Mount Sinai Hospital, Cleveland, USA) and neurology (Cleveland Clinic, Ohio, USA), he served from1984 to 2014 as Staff Neurologist at Mellen Center for MS Treatment and Research, and from 2005 to 2014 as Director of the Neuroinflammation Research Center, both at the Cleveland Clinic. His research laboratory investigates neuroinflammation across the spectrum of neurological disease with a particular focus on neurodegeneration.

  • Burkhard Becher

    Burkhard Becher is full professor and Chairman of the Institute of Experimental Immunology at the University of Zurich, Switzerland. He studied Biology at the University of Cologne, Germany, and started his graduate studies at McGill University, Montreal, Quebec, Canada, where he studied microglia biology, followed by postdoctoral research at Dartmouth Medical School, Hanover, New Hampshire, USA, where he learned the use of in vivo models of disease. His laboratory's research focuses on the role of cytokines in inflammation using primarily animal models of autoimmunity but also preclinical models of cancer. Burkhard Becher's homepage.

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