Mulberroside A: A Multi-Target Neuroprotective Agent in Alzheimer’s Disease via Cholinergic Restoration and PI3K/AKT Pathway Activation
Simple SummaryAlzheimer’s disease is a severe, gradually worsening brain disorder leading to memory loss and dementia, with no effective treatments currently available. In this study, we investigated a natural compound called mulberroside A, derived from the mulberry plant, to determine its potential protective effects against Alzheimer’s disease. Utilizing a mouse model and human brain cells, we discovered that mulberroside A enhanced memory and decreased brain cell damage. Additionally, it increased the levels of crucial brain chemicals, facilitating better communication between nerve cells. Moreover, it alleviated harmful stress in the brain and reduced the formation of two hallmark pathologies: toxic tau protein tangles and amyloid plaques. The compound significantly decreased phosphorylated tau—a key driver of neuronal degeneration—while simultaneously inhibiting amyloid plaque formation. Mulberroside A operated by activating specific neuroprotective pathways that promote brain health, including those that encourage nerve growth. These findings indicate it could serve as a promising new treatment to slow or prevent Alzheimer’s disease by targeting multiple disease mechanisms.Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)—a bioactive glycoside fromMorus albaL.—present promising alternatives. This study investigated MsA’s neuroprotective potential using scopolamine-induced AD-like mice and N2a/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-β (Aβ) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and γ-secretase components. Mechanistically, these multi-target benefits were mediated by MsA’s activation of the PI3K/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3β—directly reduced tau hyperphosphorylation—and activation of CREB/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, Aβ accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy.
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