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

Abstract

Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer’s pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation. APP/PS1 mice and N2a cells were treated with D-ribose, BBR, and mitophagy inhibitor Mdivi-1 to observe their effects on mitochondrial morphology, mitophagy, neuron histology, AD pathology, animal behavior, and PINK1 methylation. The results showed that D-ribose induced mitochondrial dysfunction, mitophagy damage, and cognitive impairment. However, BBR inhibition of PINK1 promoter methylation can reverse the above effects caused by D-ribose, improve mitochondrial function, and restore mitophagy through the PINK1–Parkin pathway, thus reducing cognitive deficits and the burden of AD pathology. This experiment puts a new light on the mechanism of action of D-ribose in cognitive impairment and reveals new insights in the use of BBR for AD treatment.

Berberine Induces Mitophagy through Adenosine Monophosphate-Activated Protein Kinase and Ameliorates Mitochondrial Dysfunction in PINK1 Knockout Mouse Embryonic Fibroblasts

“…An increase in the levels of mitophagy regulators, including LC3-II, PINK1, Parkin, and autophagosomes, has been observed upon berberine treatment in various experimental settings, for example, in a heart failure animal model, in influenza virus-infected macrophages, and in an acute kidney injury mouse model [ 33 , 34 , 35 ]. In addition, Wang et al recently showed that berberine stimulates mitophagy through the inhibition of PINK1 promoter methylation [ 36 ]. These results suggest that berberine may promote mitophagy activity through various mechanisms in different cellular contexts.…”

Berberine: A Multi-Target Natural PCSK9 Inhibitor with the Potential to Treat Diabetes, Alzheimer’s, Cancer and Cardiovascular Disease

“…80 In APP/PS1 mice and neuroblastoma-2a (N2a) cells, berberine reversed D-ribose-induced mitochondrial dysfunction, mitophagy damage, and the resulting cognitive impairment. 81 It also reduced tau hyperphosphorylation and cytotoxicity caused by Calyculin A in N2a cells. 82 The inflammatory cytokines IL-6, TNF-α, IL-1β and TLR4 are also implicated in CVD.…”

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

“…Synaptic structural and functional impairment is a typical pathological feature of AD, and normal mitochondrial function is crucial for synaptic function and plasticity as they are necessary for maintaining cellular energy supply, regulating redox signalling, and inter‐synaptic information transmission and vesicle release. Research indicates that berberine can improve mitochondrial autophagy damage, mitochondrial dysfunction, and cognitive impairments induced by D‐ribose through the PINK1‐Parkin pathway 95,96 . Another study demonstrated that in Aβ 1‐42 ‐induced primary cultured hippocampal neurons, berberine, by protecting ΔΨm and preventing a decrease in adenosine triphosphate, increases axonal mitochondrial density and length, improves mitochondrial motility and transport, and alleviates axonal mitochondrial abnormalities, thus ameliorating synaptic damage.…”