Abstract
White matter lesions (WMLs) caused by cerebral chronic hypoperfusion (CCH) may contribute to the pathophysiology of Alzheimer’s disease (AD). However, the underlying mechanisms and therapeutic approaches have yet to be totally identified. In the present study, we investigated a potential therapeutic effect of the free radical scavenger edaravone (EDA) on WMLs in our previously reported novel mouse model of AD (APP23) plus CCH with motor and cognitive deficits. Relative to AD with CCH mice at 12 months (M) of age, EDA strongly improved CCH-induced WMLs in the corpus callosum of APP23 mice at 12 M by improving the disruption of white matter integrity, enhancing the proliferation of oligodendrocyte progenitor cells, attenuating endothelium/astrocyte unit dysfunction, and reducing neuroinflammation and oxidative stress. The present study demonstrates that the long-term administration of EDA may provide a promising therapeutic approach for WMLs in AD plus CCH disease with cognitive deficits.
Highlights
White matter lesions (WMLs) have increasingly raised attention to the pathophysiological progress of ischemic stroke,[1] chronic cerebral hypoperfusion (CCH),[2,3] Alzheimer’s disease (AD),[4] and vascular dementia.[5,6,7] This is partly due to damage of components of cerebral white matter (CWM) under pathophysiological conditions.[8]
The principal findings of the present study were that EDA significantly improved damaged myelin (Figure 1), attenuated the disruption of WM integrity at internodal, paranodal, and Ranvier’s nodal sites (Figure 1), enhanced the number of oligodendrocytes and the proliferation of oligodendrocyte progenitor cells (Figure 2), inhibited damage and remodeling of endothelium/astrocyte units (Figure 3), and attenuated inflammation and oxidative stress in corpus callosum (CC) of AD þ CCH mice at 12 M (Figure 4)
The LDF result showed that the value of cerebral blood flow (CBF) in APP23 þ CCH þ EDA mice was relatively higher than that in APP23 þ CCH mice at 12 M indicating that EDA significantly recovered CBF in APP23 þ CCH mice at 12 M (Supplemental Figure 1)
Summary
White matter lesions (WMLs) have increasingly raised attention to the pathophysiological progress of ischemic stroke,[1] chronic cerebral hypoperfusion (CCH),[2,3] Alzheimer’s disease (AD),[4] and vascular dementia.[5,6,7] This is partly due to damage of components of cerebral white matter (CWM) under pathophysiological conditions.[8] The majority of CWM is composed of oligodendrocytes (OLs), a lipid-rich myelin sheath, and neuronal axons which are susceptible to oxidative stress and inflammation, but are an abundant source of reactive free radicals.[9,10] Our previous study reported that severe WMLs displayed a disruption of white matter (WM) integrity while inflammation occurred in the corpus callosum (CC) of a novel mouse model that combines AD with CCH.[11,12] specific molecular mechanisms associated with WMLs and effective therapeutic approaches to WMLs in the present AD plus CCH mouse model have not yet been fully identified.
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