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Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional
pathways. Therefore, a sophisticated treatment strategy that simultaneously targets
multiple brain cell types and disease pathways could be advantageous for effective
intervention. To elucidate an effective treatment, we developed an in vitro high-throughput
screening (HTS) assay to evaluate candidate drugs for their ability to enhance the
integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-β (Aβ)
using a cell-based BBB model. Results from HTS identified etodolac and α-tocopherol
as promising drugs for further investigation. Both drugs were tested separately and
in combination for the purpose of targeting multiple pathways including neuroinflammation
and oxidative stress. In vitro studies assessed the effects of etodolac and α-tocopherol
individually and collectively for BBB integrity and Aβ transport, synaptic markers
and Aβ production in APP-transfected neuronal cells, as well as effects on inflammation
and oxidative stress in astrocytes. Transgenic 5XFAD mice were used to translate in
vitro results of etodolac and α-tocopherol independently and with concurrent administration.
Compared to either drug alone, the combination significantly enhanced the BBB function,
decreased total Aβ load correlated with increased expression of major transport proteins,
promoted APP processing towards the neuroprotective and non-amyloidogenic pathway,
induced synaptic markers expression, and significantly reduced neuroinflammation and
oxidative stress both in vitro and in vivo. Collective findings demonstrated the combination
produced mixed interaction showing additive, less than additive or synergistic effects
on the evaluated markers. In conclusion, this study highlights the significance of
combination therapy to simultaneously target multiple disease pathways, and suggest
the repurposing and combination of etodolac and α-tocopherol as a novel therapeutic
strategy against AD.