Background: Alzheimer's disease (AD) is characterized by neuroinflammation, amyloid-β (Aβ) accumulation, and abnormal microtubule-associated protein tau (Tau) phosphorylation. This study evaluates the therapeutic potential of pterostilbene (PTS), a natural compound with anti-inflammatory activity, in an Aβ1-42-induced AD mouse model.

Methods: AD mice were established by intraperitoneal injection of aggregated Aβ1-42 and were subsequently treated with PTS, donepezil, or PTS combined with a β-site amyloid precursor protein–cleaving enzyme 1 (BACE1) upregulating agent. Cognitive performance was assessed through behavioral tests, and AD-related pathology was evaluated using Enzyme-linked immunosorbent assay (ELISA), immunofluorescence, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and Western blotting.

Results: Compared with AD mice, PTS treatment significantly improved cognitive performance in behavioral tests (p < 0.01), reduced hippocampal Aβ immunoreactive deposition and decreased soluble and insoluble Aβ40/42 levels (p < 0.01), and markedly inhibited Tau phosphorylation at Ser396 and Thr231 (p < 0.01). PTS also significantly suppressed neuroinflammatory responses, as evidenced by reduced levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), together with downregulation of microglia- and astrocyte-associated proteins (p < 0.01). At the molecular level, PTS was associated with reduced expression of BACE1, Clathrin, and Nicastrin as well as inhibition of the nuclear factor kappa B (NF-κB) pathway, as reflected by decreases in NF-κB p65 subunit (p65) and phosphorylated inhibitor of nuclear factor kappa B alpha (p-IκBα) levels, along with restoration of IκBα expression (p < 0.01). Co-treatment with the BACE1 upregulation–associated agent partially attenuated the protective effects of PTS.

Conclusion: PTS exerts significant neuroprotective effects in an Aβ1-42-induced AD mouse model by alleviating cognitive impairment, amyloidogenic pathology, neuroinflammation, and Tau hyperphosphorylation, potentially through modulation of BACE1-related processes and NF-κB signaling. PTS may represent a promising multi-target therapeutic candidate for AD.