Acori tatarinowii Rhizoma-Curcumae Radix herbal pair ameliorates cognitive impairment and suppresses neuro-inflammation via Ca2+/CaMKKβ/AMPK/mTOR pathway in Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Effective activation of neuronal autophagy and clearance of amyloid-beta (Aβ) represents a promising therapeutic strategy in the treatment of Alzheimer's disease (AD). The Acori Tatarinowii Rhizoma-Curcumae Radix Herbal pair (ACHP), derived from the traditional Changpu Yujin Decoction, has a long history in Traditional Chinese Medicine for addressing conditions related to cognitive function. However, the precise mechanisms underlying its role in autophagic dysfunction-related dementia remain unclear. AIM OF THE STUDY: This study aims to investigate the neuroprotective effects of ACHP and the underlying mechanisms in AD. MATERIALS AND METHODS: Analysis of prototype constituents in drug-containing serum was performed using UHPLC-Triple-TOF/MS. The neuroprotective effects of ACHP were evaluated in APP/PS1 mice using behavioral tests, including the Y-maze and Morris water maze. Transcriptomic analysis was conducted to identify potential neuroprotective pathways activated by ACHP. Neuronal damage and structural recovery were assessed through HE and Nissl staining. In addition, the anti-inflammatory and autophagy-regulating effects of ACHP were further investigated in N2a/APP cells. The molecular mechanisms were further elucidated using Western blot, immunofluorescence, ELISA, and qRT-PCR in both in vivo and in vitro models. RESULTS: Twenty-five compounds in ACHP-treated mouse serum were identified. ACHP improved spatial learning and memory performance, increased intracellular Ca2+ levels and downregulated the expressions of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, while significantly promoting autophagy. ACHP increased CaMKKβ protein expression and activated the AMPK signaling pathway (elevated p-AMPK/AMPK ratio), as well as those of autophagy-related proteins, while improving neuronal morphology. CONCLUSION: These findings indicate that ACHP alleviates neuro-inflammatory damage and cognitive impairment potentially through modulation of the Ca2+/CaMKKβ-AMPK-mTOR signaling pathway involved in autophagy.