Abstract: Alzheimer’s disease (AD) is a significant health challenge in the 21st century. In
spite of the approval of many new disease-modifying therapies for AD, the clinical advantages
of these new treatments are less certain. Aim: This investigation was intended
to determine the potential neuroprotective impact of morin hydrate (MH), zeolite clinoptilolite
(ZC), and/or physical and mental activities (PhM) on an aluminum chloride
(AlCl3)-induced AD rat model. Methods: Male Sprague Dawley rats were randomly allocated
into seven groups. Group I was the control group. Groups II–VII were treated
with AlCl3 for 5 weeks. Groups III–VII were tested for the effects of MH, ZC, and/or PhM.
Biochemical, brain histopathological, and behavioral studies were performed. Results:
PhM, MH, and ZC combined therapy exhibited a significant neuroprotective effect
demonstrated by corrected catecholamines and tau and β-amyloid levels, as well as the
antioxidant and anti-ferroptotic effects probably through Nrf2/HO-1/GPX4 and ACSL4
signaling pathways. In addition, combined therapy counteracted the inflammatory responses
through modulating the TLR4/NF-κβ/NLRP3 inflammasome expression.
Moreover, combined therapy groups showed the maximum improvement of both APOE4/
LRP1 and Wnt3/β-catenin/GSK-3β signaling expressions. Conclusion: This research
highlights the neuroprotective impact of MH and ZC plus PhM against AlCl3-induced
AD via modulation of Nrf2/HO-1/GPX4, TLR4/NF-κβ/NLRP3, APOE4/LRP1, and
Wnt3/β-catenin/GSK-3β signaling pathways. It is the first to point out the inclusion of