Key Points
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Alzheimer's disease affects more than 20 million people worldwide and is characterized by progressive memory deficits, cognitive impairment and personality changes. It is believed that the main cause of Alzheimer's disease is increased production and accumulation of amyloid-β peptide (amyloid-β1–42).
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Although inflammation had not been viewed as a hallmark of Alzheimer's disease, amyloid-β deposition activates a potentially pathological innate immune response, including complement, microglial-cell activation and astrocyte proliferation.
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There is a reduced prevalence of Alzheimer's disease among chronic users of non-steroidal anti-inflammatory drugs (NSAIDs). This might be due to the effects of NSAIDs on the protease that generates amyloid-β1–42 from amyloid precursor protein rather than to anti-inflammatory effects.
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Immunotherapy in mouse models of Alzheimer's disease by active immunization of amyloid-β or by passive administration of amyloid-β-specific antibodies markedly reduces amyloid-β levels in the brain and reverses behavioural impairment.
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A human clinical trial of amyloid-β immunization led to meningoencephalitis in some patients with Alzheimer's disease and was discontinued. Nevertheless, in a subset of the clinical trial participants, those with plaque-reactive amyloid-β-specific antibodies in the plasma had a significantly slower rate of cognitive decline than those patients that did not have detectable amyloid-β- specific antibodies.
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Microglial cells represent a natural mechanism by which protein aggregates and debris can be removed from the brain, and there are multiple routes by which resident microglial cells can be activated to promote clearance of amyloid-β. Evidence from animal models and patients with Alzheimer's disease indicates that microglial-cell activation can lead to amyloid-β clearance.
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Although there is no clear T-cell response in the brains of patients with Alzheimer's disease, understanding T-cell responses and adaptive immunity has become important in the immunotherapy of Alzheimer's disease. Induction of appropriate T-cell subsets might have a central role in non-antibody-mediated clearance of amyloid-β, most probably by stimulating microglial cells.
Abstract
Although Alzheimer's disease is considered to be a degenerative brain disease, it is clear that the immune system has an important role in the disease process. As discussed in this Review, immune-based therapies that are designed to remove amyloid-β peptide from the brain have produced positive results in animal models of the disease and are being tested in humans with Alzheimer's disease. Although immunotherapy holds great promise for the treatment of Alzheimer's disease, clinical trials of active amyloid-β vaccination of patients with Alzheimer's disease were discontinued after some patients developed meningoencephalitis. New immunotherapies using humoral and cell-based approaches are currently being investigated for the treatment and prevention of Alzheimer's disease.
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Acknowledgements
We are grateful to D. Selkoe and to J. El Khoury for discussions and critical review of the manuscript. This work is supported by grants from the National Institute of Ageing, National Institutes of Health (to H.L.W.), Alzheimers' Association (to H.L.W and D.F) and a Human Frontier Science Program Fellowship (to D.F.).
In Table 2, the references were missing for the fifth and ninth rows; the fifth row reference should be 139 and the ninth row reference should be 102. This error has since been corrected in the HTML and PDF versions of this article.
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Glossary
- Neurofibrillary tangles
-
Neurofibrillary tangles are pathological protein aggregates found in neurons of patients with Alzheimer's disease. Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as Tau, causing it to aggregate in an insoluble form.
- Association cortices
-
The neocortical regions that are not involved in primary sensory or motor processing. They include frontal areas subserving executive functions and temporoparietal areas supporting visuospatial processing.
- Amyloid
-
A general term for a variety of protein aggregates that accumulate as extracellular fibrils of 7–10 nm. They have common structural features, including a β-pleated sheet conformation and the ability to bind dyes such as Congo Red.
- Astrocyte
-
A star-shaped glial cell of the central nervous system that forms a structural and functional interface between non-nervous tissues and neurons. Once activated, astrocytes express glial fibrillary acidic protein at the cell surface.
- Microglial cell
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A macrophage-lineage cell that is derived from bone marrow and is present in the central nervous system.
- Tau
-
A neuronal protein that binds to microtubules, promoting their assembly and stability.
- Amyloid precursor protein
-
A membrane glycoprotein component of fast axonal transport, from which amyloid-β is cleaved by proteolytic processing.
- Limbic system
-
A collection of cortical and subcortical structures important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala.
- Amyloid fibrils
-
Structures formed by many disease-causing proteins when they aggregate. Amyloid fibrils share common biochemical characteristics such as detergent insolubility, high β-pleated sheet content and a cross β-structure, protease resistance and the ability to bind lipophilic dyes, such as Congo Red, Thioflavin S and Thioflavin T.
- Cerebral amyloid angiopathy
-
A condition in which there is a deposition of amyloid-β1–40 in the walls of the arteries that supply the brain.
- Amyloid plaques
-
Sites of amyloid-β accumulation and dystrophic neurites in the brains of mouse models and patients with Alzheimer's disease.
- Dystrophic neurites
-
Abnormal swelling that develops secondary to neuronal-cell stress in Alzheimer's disease and other neurodegenerative diseases.
- Ramified process
-
Filamentous branches from the cell body that occur in association with activation of astrocytes and microglial cells.
- Soma
-
The largest part of a cell, the cell body of a microglial cell or astrocyte.
- Astrogliosis
-
An increase in the number of astrocytes owing to proliferation at sites of damage in the central nervous system.
- Gliosis
-
The excess growth of neuroglial cells in the brain that usually follows neuronal-cell death and might lead to the formation of scar tissue.
- Fluid percussion injury
-
Increase of fluid in the brain cranial cavity, leading to brain injury.
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Weiner, H., Frenkel, D. Immunology and immunotherapy of Alzheimer's disease. Nat Rev Immunol 6, 404–416 (2006). https://doi.org/10.1038/nri1843
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DOI: https://doi.org/10.1038/nri1843
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