Biomedical Updates

Berberine is Very
Promising for Alzheimer’s

Berberine has been found to possess multiple pharmacological effects: it can inhibit acetylcholinesterase, reduce cholesterol and glucose levels, exhibit anti-inflammatory properties, and induce improved survival, development, and function of neurons, while protecting these electrically excitable brain cells.

Furthermore, it has also been demonstrated that berberine can reduce the production of amyloid-beta 40–42* (Aβ40–42) plaque, which plays a primary and critical role in the neurological degradation that hits bottom in Alzheimer’s disease. In a new study, the mechanism by which berberine accomplishes this anti-Alzheimer’s activity has been clarified.1 Berberine not only significantly decreases the production of Aβ40–42 and the expression of β-secretase (BACE)—that enable the utility of Alzheimer’s amyloid precursor—it also activates extracellular signal-regulated kinase1/2 ERK1/2), which contributes to the formation of neurofibrillary tangles, another hallmark of Alzheimer’s. The researchers’ data indicate that berberine decreases production of 40–42 by inhibiting the BACE expression via activation of the ERK1/2 pathway.

* The two isoforms of Aβ most associated with the Alzheimer’s disease are Aβ40 and Aβ42.

† Beta-secretase 1 (BACE1), also known as beta-site APP cleaving enzyme 1
(beta-site amyloid precursor protein cleaving enzyme 1).

As we know, Alzheimer’s disease is the most prominent form of senile dementia. In the pathogenesis of Alzheimer’s, Aβ plays a critical and primary role. The aggregation and accumulation of extracellular and intracellular Aβ40–42 impairs synaptic plasticity and memory. Aβ40–42 is generated by BACE and β-secretase-mediated sequential cleavages of amyloid precursor protein (APP). Inhibition of the production of 40–42 can be expected to delay the development of Alzheimer’s.

Anti-Alzheimer’s Effects of NSAIDs and Statins

Interestingly, some nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the production of 40–42 by inhibiting the expression of BACE, the activity of β-secretase via activating peroxisome proliferator-activated receptor α (PPARα), and the Rho-Rho associated kinase (Rho-ROCK) pathway. But NSAIDs have side effects, some of which can be problematic. Additionally, some statins have been found to reduce levels of 40–42 by promoting the expression of β-secretase and inhibiting BACE. Statins also have serious side effects.

The researchers’ data indicate that
berberine decreases production of
40–42 by inhibiting the BACE
expression via activation of the
ERK1/2 pathway.

Berberine, an isoquinoline alkaloid, has a long history in China as a non-prescription drug for the treatment of diarrhea and gastrointestinal disorders. And in recent years, many studies have indicated that berberine has other powerful effects, including its use as a novel cholesterol-lowering nutrient with a different mechanism than the statin family. It works by increasing the expression of low-density lipoprotein receptors (LDLR) and inhibiting lipid synthesis.

Berberine can also improve insulin resistance and exerts an insulin-independent glucose-lowering effect, stimulating insulin secretion and sensitizing insulin activity, inducing glycolysis, and increasing glucose transport and uptake activity. Some studies have even found that berberine exerts anti-inflammatory effects through a variety of mechanisms.

Berberine Benefits the Brain

Of interest, berberine can pass through the blood-brain barrier, and has multiple pharmacological properties in the brain, including neuroprotective and neurotrophic effects. A prior study has reported that berberine can decrease the production of Aβ40–42, but the mechanism remains unclear. Consequently, in the current study, the researchers focused on the mechanism of berberine on BACE and Aβ40–42 inhibition, using a line of kidney cells transfected with an Aβ-producing mutation.

Berberine Inhibits Aβ through the ERK1/2 Pathway

In this study, the researchers observed that berberine significantly decreased the production of 40–42 and the expression of BACE via activation of the ERK1/2 pathway in a dose- and time-dependent manner. The researchers also found that an antagonist of ERK1/2 pathway, abolished the effects of berberine on both 40–42 and BACE. Berberine had previously been demonstrated to be able to reduce cancerous conditions by inhibiting the proliferation of tumor cells, but the researchers did not find berberine to inhibit the proliferation and show cytotoxicity toward the kidney cell line.

Not the Anti-Proliferative or Cytotoxic Qualities of Berberine

Ergo, the inhibition of berberine on the production of 40–42 is unlikely to be associated with the anti-proliferative or anticytotoxic qualities of berberine. The enzyme BACE is crucial to the production of 40–42 and the expression of BACE increases in the brains of AD patients. Accordingly, BACE has been considered as a therapeutic target for Alzheimer’s treatments. On the other hand, the expression and activity of BACE is regulated by the ERK1/2 pathway in a dose- and time-dependent manner, and berberine increases the expression of LDLR and glucose uptake by activating the ERK1/2 pathway.

Therefore, berberine-induced reduction of BACE1 protein levels is related to ERK1 activation. Furthermore, though berberine has been shown to be unable to inhibit the activity of BACE in vitro, the ERK1/2 pathway negatively modulates BACE1 activity in vivo. Thus, the researchers think that berberine might also decrease the production of 40–42 by inhibiting BACE1 activity via activating the ERK1/2 9 pathway.

At the same time, berberine may decrease the production of 40–42 by affecting the activity of α-secretase and γ-secretase, another protein “snipper.” Together, these two secretases produce the clumps called ‘“plaques” in Alzheimer’s disease. It has been reported that ERK1/2 is an endogenous negative regulator of γ-secretase activity, and NSAIDs can inhibit γ-secretase activity by inhibiting the Rho-ROCK pathway. Berberine inhibits tumor cell migration by inhibiting the Rho-ROCK pathway in HONE1 cells, an epithelial tumor cell line, so it is possible that berberine inhibits the activity of γ-secretase by activating the ERK1/2 pathway and inhibiting the Rho-ROCK pathway. Moreover, berberine, an acetylcholinesterase inhibitor, may be able to upregulate α-secretase activity by promoting the translocation of α-secretase to the cell surface.

In the current study, once again, the researchers demonstrated that berberine can decrease the production of 40–42 by inhibiting the expression of BACE via activation of the ERK1/2 pathway. In previous studies, they had demonstrated that berberine improved impaired spatial memory and increased both the activation of microglia and the expression of insulin degrading enzyme in the rat model of Alzheimer’s. Other researchers have demonstrated other pharmacological effects of berberine in kidney cells, e.g., inhibiting Aβ42 aggregation and attenuating the Tau hyperphosphorylation. In conclusion, the researchers state that “berberine to be a very promising drug for use in Alzheimer’s patients.” Of course, we know that it’s a nutrient.


  1. Zhu F, Wu F, Ma Y, Liu G, Li Z, Sun Y, Pei Z. Decrease in the production of beta-amyloid by berberine inhibition of the expression of beta-secretase in HEK293 cells. BMC Neurosci 2011 Dec 12;12(1):125.

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