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Granulocyte colony stimulating factor decreases brain amyloid burden and reverses
cognitive impairment in Alzheimer s mice
#MMPMID19500657
Sanchez-Ramos J
; Song S
; Sava V
; Catlow B
; Lin X
; Mori T
; Cao C
; Arendash GW
Neuroscience
2009[Sep]; 163
(1
): 55-72
PMID19500657
show ga
Granulocyte colony stimulating factor (G-CSF) is a multi-modal hematopoietic
growth factor, which also has profound effects on the diseased CNS. G-CSF has
been shown to enhance recovery from neurologic deficits in rodent models of
ischemia. G-CSF appears to facilitate neuroplastic changes by both mobilization
of bone marrow-derived cells and by its direct actions on CNS cells. The overall
objective of the study was to determine if G-CSF administration in a mouse model
of Alzheimer's disease (AD) (Tg APP/PS1) would impact hippocampal-dependent
learning by modifying the underlying disease pathology. A course of s.c.
administration of G-CSF for a period of less than three weeks significantly
improved cognitive performance, decreased beta-amyloid deposition in hippocampus
and entorhinal cortex and augmented total microglial activity. Additionally,
G-CSF reduced systemic inflammation indicated by suppression of the production or
activity of major pro-inflammatory cytokines in plasma. Improved cognition in AD
mice was associated with increased synaptophysin immunostaining in hippocampal
CA1 and CA3 regions and augmented neurogenesis, evidenced by increased numbers of
calretinin-expressing cells in dentate gyrus. Given that G-CSF is already
utilized clinically to safely stimulate hematopoietic stem cell production, these
basic research findings will be readily translated into clinical trials to
reverse or forestall the progression of dementia in AD. The primary objective of
the present study was to determine whether a short course of G-CSF administration
would have an impact on the pathological hallmark of AD, the age-dependent
accumulation of A beta deposits, in a transgenic mouse model of AD (APP+ PS1;
Tg). A second objective was to determine whether such treatment would impact
cognitive performance in a hippocampal-dependent memory paradigm. To explain the
G-CSF triggered amyloid reduction and associated reversal of cognitive
impairment, several mechanisms of action were explored. (1) G-CSF was
hypothesized to increase activation of resident microglia and to increase
mobilization of marrow-derived microglia. The effect of G-CSF on microglial
activation was examined by quantitative measurements of total microglial burden.
To determine if G-CSF increased trafficking of marrow-derived microglia into
brain, bone marrow-derived green fluorescent protein-expressing (GFP+) microglia
were visualized in the brains of chimeric AD mice. (2) To assess the role of
immune-modulation in mediating G-CSF effects, a panel of cytokines was measured
in both plasma and brain. (3) To test the hypothesis that reduction of A beta
deposits can affect synaptic area, quantitative measurement of synaptophysin
immunoreactivity in hippocampal CA1 and CA3 sectors was undertaken. (4) To learn
whether enhanced hippocampal neurogenesis was induced by G-CSF treatment, numbers
of calretinin-expressing cells were determined in dentate gyrus.
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