Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

Abstract

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid ␤ and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2-to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation.

Glial scars are permeable to the neurotoxic environment of chronic stroke infarcts

“…Physical disruption caused by the stroke disconnects many neurons and may cause transneuronal degeneration (Fornito et al, 2015). Physical disruption may also reduce the effectiveness of the paravascular space to remove metabolic waste products and other potentially neurotoxic interstitial solutes from the interstitial fluid in the ipsilateral hemisphere (Wang et al, 2017). These mechanisms almost certainly also contribute to delayed neurodegeneration following stroke.…”

The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future

“…Further, pretreatment of wildtype mice with Aβ led to significant suppression of CSF tracer influx, suggesting that not only does AD lead to reduced glymphatic clearance and accumulation of Aβ, but that this Aβ aggregation will feed forward and produce further glymphatic slowing (59). Decreased glymphatic influx has also been observed secondary to subarachnoid hemorrhage, acute ischemia, and multiple micro-infarction (60, 61). Interestingly, in the case of multiple small embolic strokes, while glymphatic perfusion spontaneously recovers by 14 days, there is persistent solute trapping within lesion cores, potentially explaining the clinical connection between this disease, Aβ plaque formation, and long-term neurodegeneration (61).…”

“…Decreased glymphatic influx has also been observed secondary to subarachnoid hemorrhage, acute ischemia, and multiple micro-infarction (60, 61). Interestingly, in the case of multiple small embolic strokes, while glymphatic perfusion spontaneously recovers by 14 days, there is persistent solute trapping within lesion cores, potentially explaining the clinical connection between this disease, Aβ plaque formation, and long-term neurodegeneration (61). In the murine ‘Hit & Run’ model of traumatic brain injury (TBI), impairment of glymphatic CSF inflow to brain is seen between 1 and 28 days following injury (Fig.…”

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

“…Interestingly, pretreating young wild-type mice with Aβ suppressed glymphatic influx, suggesting that not only is Aβ aggregation a consequence of a breakdown of flow within this pathway, but it may also be an independent cause of glymphatic dysfunction (23). Further, glymphatic impairment is a prominent feature of cerebrovascular disease, including both subarachnoid hemorrhage and multiple microinfarction (24,25). Following traumatic brain injury, reduced clearance of cortical interstitial solute was associated with motor and cognitive neurological deficits (26).…”