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Abstract
<p class="first" id="d10460504e104">Among the changes that typify Alzheimer's disease
(AD) are neuroinflammation and microglial
activation, amyloid deposition perhaps resulting from compromised microglial function
and iron accumulation. Data from Genome Wide Association Studies (GWAS) identified
a number of gene variants that endow a significant risk of developing AD and several
of these encode proteins expressed in microglia and proteins that are implicated in
the immune response. This suggests that neuroinflammation and the accompanying microglial
activation are likely to contribute to the pathogenesis of the disease. The trigger(s)
leading to these changes remain to be identified. In this study, we set out to examine
the link between the inflammatory, metabolic and iron-retentive signature of microglia
in vitro and in transgenic mice that overexpress the amyloid precursor protein (APP)
and presenilin 1 (PS1; APP/PS1 mice), a commonly used animal model of AD. Stimulation
of cultured microglia with interferon (IFN)γ and amyloid-β (Aβ) induced an inflammatory
phenotype and switched the metabolic profile and iron handling of microglia so that
the cells became glycolytic and iron retentive, and the phagocytic and chemotactic
function of the cells was reduced. Analysis of APP/PS1 mice by magnetic resonance
imaging (MRI) revealed genotype-related hypointense areas in the hippocampus consistent
with iron deposition, and immunohistochemical analysis indicated that the iron accumulated
in microglia, particularly in microglia that decorated Aβ deposits. Isolated microglia
prepared from APP/PS1 mice were characterized by a switch to a glycolytic and iron-retentive
phenotype and phagocytosis of Aβ was reduced in these cells. This evidence suggests
that the switch to glycolysis in microglia may kick-start a cascade of events that
ultimately leads to microglial dysfunction and Aβ accumulation.
</p>