To determine whether S100A1 depletion in the setting of cerebrovascular ischemia causes a difference in disease burden.

S100A1 is a calcium-binding protein implicated in the etiology and anti-inflammatory modulation of several cardiovascular and neurovascular diseases. Preclinical trials using AAV9-mediated S100A1 gene therapy are shown to improve cardiac function following myocardial infarction. In acute ischemic stroke, S100A1 levels correlate with infarct volume and pro-inflammatory markers (IL-6, NF-kB), suggesting attenuation as a therapeutic target. Additionally, S100A1’s involvement in nitric oxide regulation raises questions about its role in vascular cognitive impairment and dementia (VCID), a disease with both vascular and inflammatory components. Interactions with S100B and RAGE further complicate its role in neurodegeneration. In this study, we use a preclinical model of S100A1 to investigate progression of ischemia-induced vascular dementia.

Transgenic S100A1-/- C57bl mice (as confirmed with genotyping) were subject to either bilateral carotid artery stenosis (BCAS) or control procedures. Following an 8 or 12 month period of appropriate post-surgical care, mice are subject to behavioral tests of memory, neurocognitive and motor function, including beam walk, novel object recognition, grid hang, Y-maze and open field tests. Following behavior testing, mice were sacrificed with collection of plasma, brain, heart, liver, spleen and kidney tissues for histopathological analysis. Luxol fast blue staining was done on brain tissue for assessment of demyelination injury. 

S100A1-/- mice subject to BCAS demonstrated significantly decreased neurocognitive, memory and motor function as compared to control S100A1-/- animals at both the 8 and 12 month end-points. Luxol fast blue histopathology of coronal brain sections demonstrated greater demyelinating lesion burden in white matter tracts of BCAS animals as compared to control.

S100A1 depletion may exacerbate post-infarct neurological injury in this preclinical model of ischemic stroke.