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Published on: March 17, 2016
Cognitive deficits and delayed neuronal loss in a mouse model of multiple microinfarcts
Minghuan Wang1, Jeffrey J Iliff, Yonghong Liao
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, USA.
Abstract:
Microinfarcts are a common clinical feature of the aging brain, particularly in patients with cognitive decline or vascular or Alzheimer's dementia. However, the natural history of these lesions remains largely unexplored. Here we describe a mouse (C57BL/6J) model of multiple diffuse microinfarcts induced by unilateral internal carotid artery injection of cholesterol crystals (40-70 μm). Microinfarcts were spread throughout the deep cortex, subcortical tissue, and hippocampus and were comprised of a core positive for CD68 (a marker for reactive microglia and macrophages), surrounded by large regions of glial fibrillary acidic protein-positive reactive astrogliosis. Widespread reactive gliosis, including mislocalization of the astrocytic water channel aquaporin 4 persisted long after injury, recovering only after 1 month after stroke. Within the cortex, neuronal cell death progressed gradually over the first month, from ∼35% at 3 d to 60% at 28 d after stroke. Delayed demyelination was also observed in lesions, beginning 28 d after stroke. These findings demonstrate that microinfarct development follows a distinct course compared to larger regional infarcts such as those induced by middle cerebral artery occlusion. The long-lasting gliosis, delayed neuronal loss, and demyelination suggest that the therapeutic window for microinfarcts may be much wider (perhaps days to weeks) than for larger strokes.
Insights
This study introduces a mouse model for brain microinfarcts, revealing delayed neuronal death and demyelination. These findings suggest a broader therapeutic window for microinfarcts compared to larger strokes.
Area of Science:
- Neurology
- Neuroscience
- Pathology
Background:
- Microinfarcts are common in aging brains, linked to cognitive decline and dementia.
- The natural history and progression of microinfarcts are not well understood.
- Existing research often focuses on larger stroke models, leaving microinfarcts understudied.
Purpose of the Study:
- To establish a mouse model for studying diffuse microinfarcts.
- To investigate the temporal progression of microinfarcts, including gliosis, neuronal loss, and demyelination.
- To compare the pathological course of microinfarcts to larger cerebral infarcts.
Main Methods:
- Induction of multiple diffuse microinfarcts in C57BL/6J mice via unilateral internal carotid artery injection of cholesterol crystals.
- Histological analysis using markers for microglia (CD68), reactive astrocytes (GFAP), and myelin.
- Assessment of neuronal cell death and aquaporin 4 mislocalization over time post-stroke.
Main Results:
- Microinfarcts were characterized by microglial/macrophage cores and reactive astrogliosis.
- Persistent reactive gliosis and aquaporin 4 mislocalization were observed for up to 1 month.
- Neuronal cell death progressed gradually, reaching 60% by 28 days post-stroke.
- Delayed demyelination was evident starting 28 days after the induced microinfarcts.
Conclusions:
- Microinfarct development follows a distinct timeline compared to larger infarcts.
- The observed delayed neuronal loss and demyelination suggest a potentially wider therapeutic window for microinfarcts.
- This mouse model provides a valuable tool for exploring microinfarct pathology and therapeutic strategies.
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