Cerebral autosomal dominant arteriopathy with subcortical
infarct and
leukoencephalopathy (
CADASIL) is a Notch3 mutation-induced
cerebral small vessel disease, leading to recurrent
ischemic stroke and
vascular dementia. There is currently no treatment that can stop or delay
CADASIL progression. We have demonstrated the efficacy of treatment with combined
stem cell factor (SCF) and
granulocyte colony-stimulating factor (
G-CSF) (SCF+G-CSF) in reducing cerebral small vessel
thrombosis in a TgNotch3R90C mouse model of
CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular
thrombosis-induced ischemic damage. Using
bone marrow transplantation to track
thrombosis, we observed that capillary
thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary
thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary
thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of
CADASIL. SCF+G-CSF treatment ameliorates the capillary
thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of
CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular
ischemia in
CADASIL.