How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes

Abstract

SummaryA huge amount of evidence has implicated amyloid beta (Aβ β β β ) peptides and other derivatives of the amyloid precursor protein (β β β β APP) as central to the pathogenesis of Alzheimer's disease (AD). It is also widely recognized that age is the most important risk factor for AD and that the innate immune system plays a role in the development of neurodegeneration. Little is known, however, about the molecular mechanisms that underlie age-related changes of innate immunity and how they affect brain pathology. Aging is characteristically accompanied by a shift within innate immunity towards a pro-inflammatory status. Pro-inflammatory mediators such as tumour necrosis factor-α α α α or interleukin-1β β β β can then in combination with interferon-γ γ γ γ be toxic on neurons and affect the metabolism of β β β β APP such that increased concentrations of amyloidogenic peptides are produced by neuronal cells as well as by astrocytes. A disturbed balance between the production and the degradation of Aβ β β β can trigger chronic inflammatory processes in microglial cells and astrocytes and thus initiate a vicious circle. This leads to a perpetuation of the disease.

Reduction of Amyloid Angiopathy and Aβ Plaque Burden after Enriched Housing in TgCRND8 Mice

“…Inflammation processes in AD brains lead to both enhanced cytotoxicity as well as enhanced A␤ aggregation. 28 Thus our data suggest that enrichment might reduce the release of cytotoxic agents and lower A␤ aggregation. It remains unclear to what extent the up-regulation of anti-inflammatory and down-regulation of proinflammatory mediators in enriched brains are primary cause or secondary phenomena to A␤ burden reduction.…”

The neuropathology and cerebrovascular mechanisms of dementia

“…Recent evidence suggests that hypoxia and pro-inflammatory mediators of neuroinflammation may precede A and p-tau neuropathology, 108 while others argue that neuroinflammation is found downstream of AD protein aggregation. 109,110 Hypoxia-induced inflammation has been shown to cause tissue damage and neurologic deficits in the central nervous system, correlating with an upregulation of an oxygen (O 2 )-dependent nuclear transcription factor, hypoxia-inducible factor-1 .…”

Inflammatory changes parallel the early stages of Alzheimer disease

“…Specifically, Aβ accumulation leads to a site-specific activation of glia resulting in the secretion of pro-inflammatory cytokines [3,13]. The inflammatory response may be an attempt to clear Aβ deposits; however, the progressive accumulation of Aβ and its aggregation into insoluble plaques may induce a chronic pro-inflammatory response leading to compromised neuronal function [8]. In support of a role for neuroinflammation in AD dementia, one study found a higher correlation between synapse loss and activated microglia than between Aβ deposits and NFTs [33].…”