Background: Microglial activation is a hallmark of neuroinflammation, seen in most acute
and chronic neuropsychiatric conditions. With growing knowledge about microglia functions in surveying
the brain for alterations, microglial activation is increasingly discussed in the context of disease progression
and pathogenesis of Alzheimer's disease (AD). Underlying molecular mechanisms, however,
remain largely unclear. While proper microglial function is essentially required for its scavenging duties,
local activation of the brain’s innate immune cells also brings about many less advantageous changes,
such as reactive oxygen species (ROS) production, secretion of proinflammatory cytokines or degradation
of neuroprotective retinoids, and may thus unnecessarily put surrounding healthy neurons in danger.
In view of this dilemma, it is little surprising that both, AD vaccination trials, and also immunosuppressive
strategies have consistently failed in AD patients. Nevertheless, epidemiological evidence has suggested
a protective effect for anti-inflammatory agents, supporting the hypothesis that key processes involved
in the pathogenesis of AD may take place rather early in the time course of the disorder, likely
long before memory impairment becomes clinically evident.
Activation of microglia results in a severely altered microenvironment. This is not only caused by the
plethora of secreted cytokines, chemokines or ROS, but may also involve increased turnover of neuroprotective
endogenous substances such as retinoic acid (RA), as recently shown in vitro.
Results: We discuss findings linking microglial activation and AD and speculate that microglial malfunction,
which brings about changes in local RA concentrations in vitro, may underlie AD pathogenesis
and precede or facilitate the onset of AD. Thus, chronic, “innate neuroinflammation” may provide a
valuable target for preventive and therapeutic strategies.