Subchronic diethyl phthalate exposure aggravates Alzheimer-like phenotypes in 5XFAD mice: partial attenuation by Akt activation.

Diethyl phthalate (DEP) is a ubiquitous low-molecular-weight phthalate, yet its influence on Alzheimer's disease (AD) progression remains unclear. We combined network toxicology and molecular docking with in vivo validation to determine whether subchronic DEP exposure aggravates AD-like pathology and to define the involvement of PI3K/Akt signaling. Bioinformatic analysis identified 133 shared targets between phthalate-related proteins and AD-associated genes, highlighted PI3K/Akt signaling, and nominated PIK3CA as a potential DEP-binding target. Seven-month-old male 5XFAD and wild-type mice received DEP (3,000mgkg-1 day-1 by oral gavage) for 54 days as a proof-of-principle high-dose exposure paradigm; a rescue cohort received the Akt activator SC79 (2mgkg-1 day-1 intraperitoneally for 7 days). DEP impaired spatial learning and memory without altering gross locomotor activity, increased hippocampal and cortical amyloid plaques and A11-reactive oligomers, reduced synaptic proteins, and was associated with greater hippocampal neuronal injury in 5XFAD mice. These changes were accompanied by reduced AKT and GSK3β phosphorylation, increased BACE1, altered proteostasis-associated markers, and enhanced apoptotic signaling. Pharmacological Akt activation partially restored cognitive performance, reduced amyloid burden, preserved synaptic and neuronal integrity, and partially attenuated the associated molecular alterations. Together, these findings indicate that DEP aggravates AD-like phenotypes in an amyloid-vulnerable brain, implicate Akt-centered signaling as a functionally relevant pathway, and nominate PIK3CA as a candidate molecular target linking phthalate exposure to amyloid-associated neurodegeneration.