The role of the immune system in clearance of Abeta from the brain - PubMed (original) (raw)
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The role of the immune system in clearance of Abeta from the brain
Delphine Boche et al. Brain Pathol. 2008 Apr.
Abstract
In Alzheimer's disease (AD), there is abnormal accumulation of Abeta and tau proteins in the brain. There is an associated immunological response, but it is still unclear whether this is beneficial or harmful. Inflammation in AD, specifically in the form of microglial activation, has, for many years, been considered to contribute to disease progression. However, two types of evidence suggest that it may be appropriate to revise this view: first, the disappointing results of prospective clinical trials of anti-inflammatory agents and, second, the observation that microglia can clear plaques in AD following Abeta immunization. Although Abeta immunization alters AD pathology, there is limited evidence so far of benefit to cognitive function. Immunization against microorganisms is almost always used as a method of disease prevention rather than to treat a disease process that has already started. In animal models, immunotherapy at an early age can protect against Abeta accumulation and it will be interesting to see if this can usefully be applied to humans to prevent AD.
Figures
Figure 1
Aβ immunohistochemistry in unimmunized Alzheimer's disease (AD) and after Aβ42 immunization. Pattern of Aβ immunoreactivity (pan‐Aβ antibody, residues 8–17) in the parietal lobe of an unimmunized AD case (AD) and an immunized AD case (iAD). The AD case reveals the presence of numerous Aβ plaques in the cerebral cortex, but whereas in the iAD case, the area is virtually devoid of plaques with a persistence of Aβ in the cerebral vasculature. Scale bar = 1 mm.
Figure 2
Activated microglia in Alzheimer's disease (AD) vs. immunized AD (iAD). Detection of HLA‐DR (A) and CD68 (B) positive microglia in an unimmunized AD case. After Aβ42 immunization, HLA‐DR (C) and CD68 (D) positive microglia are observed particularly clustered around residual plaques. Using isoform specific antibodies, Aβ42 (E) and Aβ40 (F) peptides are detected within microglia after Aβ42 immunization, rarely seen in unimmunized AD cases. Scale bar = 40 µm.
Figure 3
Summary of the pathological changes observed in Alzheimer's disease (AD) after Aβ42 immunization. AD pathology is characterized by the presence of Aβ plaques, dystrophic neurites, intraneuronal tangles and neuropil threads with activated microglia and cerebral amyloid angiopathy, as illustrated with modified Bielschowsky staining and in diagrammatic form (A). After Aβ42 immunization, the Aβ plaques and dystrophic neurites are removed, microglia have phagocytosed Aβ, Aβ is increased in the vasculature and the neuropil threads and tangles are still observed (B). Scale bar = 50 µm.
Figure 4
Meningoencephalitis. Features observed in one immunized patient with meningoencephalitis who came to autopsy more than 1 year later: rarefaction of white matter as detected by Kluver–Barrera staining (A), marked increase of HLA‐DR (B) and CD68 (C) positive microglia/macrophages and the presence of T lymphocytes in the leptomeninges and in relation to a cerebral blood vessel (D, anti‐CD45RO antibody). Scale bar = 50 µm.
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