Abstract
Microglia have long been noted to be present and activated in Alzheimer brain. Demonstrations that these microglia are associated with the specific lesions of Alzheimer disease—Aβ plaques and neurofibrillary tangles—and that these microglia overexpress the potent proinflammatory cytokine interleukin-1 led to the recognition of a potential pathogenic role for these cells in initiation and progression of disease. Activated, cytokine-overexpressing microglia are near-universal components of Aβ plaques at early (diffuse) and mid (neuritic) stages of progression in Alzheimer brain, and only decline in end-stage, dense core plaques. They correlate with plaque distribution across cerebral cortical cytoarchitectonic layers and across brain regions. They also show close associations with tangle-bearing neurons in Alzheimer brain. Microglial activation is a consistent feature in conditions that confer increased risk for Alzheimer disease or that are associated with accelerated appearance of Alzheimer-type neuropathological changes. These include normal ageing, head injury, diabetes, heart disease, and chronic intractable epilepsy. The neuropathological demonstration of microglial activation in Alzheimer brain and in Alzheimer-related conditions opened the field of basic and applied investigations centered on the idea of a pathogenically important neuroinflammatory process in Alzheimer disease.
Highlights
Microglia have been known to be present in the characteristic plaques of Alzheimer disease since the first descriptions of these cells by del Rio Hortega and Penfield in the 1920s [1], but half a century would pass before attention returned to these cells
The first suggestion of a causative role for microglia in Alzheimer disease came from Glenner, who hypothesized in 1979 that the amyloid found in Alzheimer brain was produced by these cells [2]
This report, together with the finding that interleukin-1 regulates the synthesis of the Aβ precursor protein [9], immediately suggested that microglia and their cytokines might play a role in driving plaque development, a concept very different from ideas about amyloid production or phagocytosis and protein degradation that had been previously attributed to microglia
Summary
Microglia have been known to be present in the characteristic plaques of Alzheimer disease since the first descriptions of these cells by del Rio Hortega and Penfield in the 1920s [1], but half a century would pass before attention returned to these cells. The first suggestion of a causative role for microglia in Alzheimer disease came from Glenner, who hypothesized in 1979 that the amyloid found in Alzheimer brain was produced by these cells [2]. This idea dominated several subsequent studies that identified microglia associated with amyloid plaques in the brains of Alzheimer patients [3,4,5]. Over the several years, additional cytokines were added to the listing of proteins that are elevated in Alzheimer brain.
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