Objective To study the effects of TYRO
protein kinase-
binding protein (TYROBP)
deficiency on
learning behavior,
glia activation and pro-inflammatory cycokines, and Tau
phosphorylation of a new
Alzheimer's disease (AD)
mouse model
carrying a PSEN1 p.G378E
mutation.
Methods A new AD
mouse model
carrying PSEN1 p.G378E
mutation was built based on our previously found AD
family which might be ascribed to the PSEN1
mutation, and then crossed with TYROBP deficient
mice to produce the heterozygous
hybrid mice (PSEN1G378E/WT; Tyrobp+/-) and the homozygous
hybrid mice (PSEN1G378E/G378E; Tyrobp-/-).
Water maze test was used to detect
spatial learning and
memory ability of
mice. After the
mice were sacrificed, the
hippocampus was excised for further
analysis.
Immunofluorescence was used to identify the
cell that expresses TYROBP and the number of
microglia and
astrocyte.
Western blot was used to detect the expression levels of Tau and phosphorylated Tau (p-Tau), and
ELISA to
measure the levels of pro-inflammatory
cytokines. Results Our results showed that TYROBP specifically expressed in the
microglia of
mouse hippocampus. Absence of TYROBP in PSEN1G378E
mutation mouse model prevented the deterioration of
learning behavior, decreased the numbers of
microglia and
astrocytes, and the levels of
interleukin-6,
interleukin-1β and
tumor necrosis factor-α in the
hippocampus (all P < 0.05). The ratios of AT8/Tau5, PHF1/Tau5, pT181/Tau5, pT231/Tau5 and p-ERK/ERK were all higher in homozygous
hybrid mice (PSEN1G378E/G378E; Tyrobp-/-
mice) compared with PSEN1G378E/G378E
mice (all P < 0.05). Conclusions TYROBP
deficiency might
play a protective
role in the modulation of
neuroinflammation of AD. However, the relationship between
neuroinflammation processes involving
microglia and
astrocyte activation, and release of pro-inflammatory
cytokines, and p-Tau
pathology needs further study.