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We sought to establish a mouse model of subcortical ischemic vascular dementia (SIVD) that develops predominant white matter (WM) injury and cognitive dysfunction induced by chronic cerebral hypoperfusion. Adult C57Bl/6 male (n = 48) mice were subjected to bilateral common carotid artery stenosis with external microcoils (inner diameters: 0.16 mm, left; 0.18 mm, right). Mice were categorized according to left-side cerebral blood flow (CBF) value on day 6 into those with severe cerebral hypoperfusion (SCH; n = 16, < 30% of preoperative CBF baseline value) or moderate cerebral hypoperfusion (MCH; n = 21, 30-50% of preoperative value). Another 15 mice were sham operated. Neurological dysfunction was evaluated by Morris water maze, rotating rod, and open field tests. Histopathological examination was performed on day 35 after surgery. MCH animals showed persistent hyperlocomotion with reduced anxiety and spatial reference memory dysfunction. Rarefaction and small necrotic lesions were predominantly confined to the WM, with reactive astrocytosis, microglial infiltration, axonal loss, and myelin disruption, and these changes were dominant on the left side. SCH animals had persistent hyperlocomotion and motor dysfunction, and their ischemic lesions extended from the WM to the hippocampus and cortex. In MCH animals, myelin basic protein and neurofilament fiber densities in the WM were correlated with the time spent in the correct area in the water maze probe trials. Our MCH mouse model with the development of several types of neurological dysfunction with high reproducibility would be useful for investigating the pathomechanisms of WM injury in human SIVD.

The lack of blood–brain barrier (BBB) penetrating ability has hindered the delivery of many therapeutic agents for tauopathy treatment. In this study, we report the synthesis of a circular bifunctional aptamer to enhance the in vivo BBB penetration for better tauopathy therapy. The circular aptamer consists of one reported transferrin receptor (TfR) aptamer to facilitate TfR-aptamer recognition-induced transcytosis across BBB endothelial cells, and one Tau protein aptamer that we recently selected to inhibit Tau phosphorylation and other tauopathy-related pathological events in the brain. This novel circular Tau–TfR bifunctional aptamer displays significantly improved plasma stability and brain exposure, as well as the ability to disrupt tauopathy and improve traumatic brain injury (TBI)-induced cognitive/memory deficits in vivo, providing important proof-of-principle evidence that circular Tau–TfR aptamer can be further developed into diagnostic and therapeutic candidates for tauopathies.

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