Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

Abstract

Background: Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology. Methods: The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry. Results: BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice. Conclusion: BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

Nmnat2 attenuates amyloidogenesis and up-regulates ADAM10 in AMPK activity-dependent manner

“…Several studies have demonstrated that activation of AMPK alleviates Aβ pathogenesis and rescues synapse damage [ 59 , 60 ]. We assumed that AMPK involves Nmnat2-mediated reduction of Aβ.…”

Berberine Rescues D-Ribose-Induced Alzheimer‘s Pathology via Promoting Mitophagy

“…Previously, our group has reported that BBR attenuates cognitive deficits and limits hyperphosphorylation of tau via inhibiting the activation of NF-kappaB signaling and retarding oxidative stress and neuro-inflammation [ 32 ]. Berberine alleviates amyloid-beta pathology in the brain of APP/PS1 mice via inhibiting beta/gamma-secretases activity, enhancing alpha-secretases [ 33 ], and activating LKB1/AMPK signaling [ 34 ]. BBR ameliorates D-ribose-induced amyloid-beta pathology via inhibiting mTOR/p70S6K signaling and improves spatial learning and memory [ 12 ].…”

Therapeutic Effects of the major alkaloid constituents of Evodia rutaecarpa in Alzheimer's disease

“…initially demonstrated that berberine can enhance autophagy activity in the brains of AD mice by increasing the activity of autophagy‐related proteins such as LC3‐II, beclin‐1, and hVPS34, thereby reducing Aβ protein levels and significantly improving spatial learning and memory retention in 3xTg AD mice 70 . Subsequently, Cai and Wang separately demonstrated that berberine can regulate autophagy activity through the LKB1/AMPK and mTOR/p70S6K pathways, ameliorating pathological damage caused by Aβ protein 84,85 . It is worth mentioning that recent research indicates that berberine can promote the expression of vascular‐related proteins such as vascular endothelial growth factor, N‐cadherin, Ang‐1, promoting microvessel formation, increasing cerebral blood flow, and accelerating Aβ protein clearance.…”