A strong relationship between Alzheimer\'s disease (AD) and vascular dysfunction has been the focus of increasing attention in aging societies. In the present study, we examined the long-term effect of scallop-derived plasmalogen (sPlas) on vascular remodeling-related proteins in the brain of an AD with cerebral hypoperfusion (HP) mouse model. We demonstrated, for the first time, that cerebral HP activated the axis of the receptor for advanced glycation endproducts (RAGE)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/provirus integration site for Moloney murine leukemia virus 1 (PIM1)/nuclear factor of activated T cells 1 (NFATc1), accounting for such cerebral vascular remodeling. Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD.

The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer\'s disease (AD) patients.
However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20-30% among the dementia society, were still elusive.
In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH.
The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-β pathology, regulated neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M.
These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH.