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Immune attack: the role of inflammation in Alzheimer disease

Key Points

  • Alzheimer disease (AD), like other proteinopathic neurodegenerative disorders, is characterized by the accumulation of amyloidogenic proteins

  • A neuroinflammatory component in AD has been known for more than a decade; however, the importance of the contribution of inflammation in the pathogenesis of AD has been appreciated only recently. Genetic and bioinformatic data from individuals with AD and insights from preclinical models now substantiate the present view that inflammation participates in and exacerbates AD pathology.

  • Neuroinflammation in AD is primarily driven by the brain's intrinsic myeloid cells (known as microglia) and escalates with disease progression; thus AD-associated neuroinflammation contrasts with traditionally defined neuroinflammatory diseases such as multiple sclerosis and encephalitides, which are mainly driven by blood-derived leukocytes and B and T lymphocytes, invading the CNS.

  • Manipulation of some of the molecules of the innate immune system or their respective pathways in animal models of AD has resulted in substantial alteration of disease pathology, indicating the potential to ameliorate the disease course through targeting components of the immune system. The immune system thus appears to provide exciting novel and accessible targets for the diagnosis, control and treatment of AD; however, precise knowledge about specific and defined immune events, which may change during the disease course or differ among individuals with AD, is required.

  • Diagnostics research needs to develop sensitive methods to detect immune alterations prior to the onset of AD to identify those patients at risk who may benefit most from specific, tailored anti-inflammatory interventions.

Abstract

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.

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Figure 1: Pathological events in Alzheimer disease and microglial priming.
Figure 2: Distinguishing neuroinflammation: innate immune-driven versus adaptive immune-driven neuro-inflammation.
Figure 3: Dynamic, multifaceted interactions with amyloid-β mediate microglial phenotypes in Alzheimer disease.
Figure 4: Proposed Aβ-dependent CNS specific non-adaptive IL-12 and IL-23 actions in AD.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB TRR 43, NeuroCure Exc 257 and HE 3130/6-1 to FLH), the Federal Ministry of Education and Research (DLR/BMBF; Kompetenznetz Degenerative Demenzen), the European Union ITN-NeuroKine project, and a Collaborative Research Grant of the Berlin Institute of Health (BIH) to F.L.H. Work in the Ransohoff lab has been supported by the U. S. National Institutes of Health, the National Multiple Sclerosis Society, the Williams Family Fund for MS Research and the Guthy Jackson Charitable Foundation. Work in the Becher lab is supported by grants from the Swiss National Science Foundation (316030_150768, 310030_146130 and CRSII3_136203), European Union FP7 project TargetBraIn, NeuroKine and ATECT, and the university research priority project translational cancer research.

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Correspondence to Frank L. Heppner, Richard M. Ransohoff or Burkhard Becher.

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Competing interests

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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Glossary

Myeloid cells

The subset of leukocytes that are not lymphocytes. They include granulocytes, monocytes, macrophages and dendritic cells.

Familial AD

An uncommon form of AD that usually occurs before the age of 65 and is inherited in an autosomal dominant fashion.

Microglia activation

A term used to describe a functional activation of microglial cells, for example, in response to a defined stimulus in pathophysiological settings or during development; however, it is often used to describe a change in the morphological appearance of microglia that does not necessarily correspond to the functional status of these cells. Reactive microglia is a term used when microglia respond to pathological changes and deviate from the normal steady-state.

Encephalitides

Acute inflammatory diseases of the brain, typically consisting of tissue-invading leukocytes (mainly T cells).

Quantitative trait loci

Stretches of DNA that contain or are linked to the genes that underlie a quantitative trait. Quantitative traits refer to certain phenotypes.

Cerebral amyloidosis

This term describes all forms of CNS diseases that feature the deposition of proteins (so-called proteinopathies).

Hypertrophy

The increase in the volume of an organ, tissue or cell.

Apolipoprotein E

(APOE). A class of apolipoprotein that is required for the catabolism of triglyceride-rich lipoprotein constituents. In the CNS, APOE is generated primarily by astrocytes, and transports cholesterol to neurons via APOE receptors, whereas in the periphery, APOE is mainly produced by the liver and macrophages, and mediates cholesterol metabolism.

Neurovascular unit

(NVU). This consists of vascular cells such as brain endothelial cells, pericytes and vascular smooth muscle cells, glial cells such as astrocytes, microglia and oligodendroglia, and neurons. It links neural activity to blood flow and controls the exchange of biologically relevant protein interactions between brain and the periphery.

Adaptive immune system

The immune system that forms the basis for acquired immunity and immunological memory and involves T and B lymphocytes.

Mast cells

These are resident granulocytes of several types of tissues containing many granules rich in histamine and heparin.

Biologicals

Medicinal products that are manufactured in or extracted from biological sources (they may also be termed biopharmaceutical or biologic medical products); they are distinct from chemically synthesized pharmaceutical products.

NLRP3 inflammasome

Inflammasomes comprise a sensor molecule from the NOD-like receptor (NLR) family or the pyrin and HIN domain-containing protein (PYHIN) family, the adaptor protein ASC and caspase 1. The NALP3 inflammasome is expressed in myeloid cells, senses a wide range of aggregated molecules, and promotes the maturation of the inflammatory cytokines interleukin-1 (IL-1) and IL-18.

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Heppner, F., Ransohoff, R. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16, 358–372 (2015). https://doi.org/10.1038/nrn3880

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