April 23, 2024

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Metformin: Potential Harm to Brain Cognitive Function and Aggravating Alzheimer’s Pathology

Metformin: Potential Harm to Brain Cognitive Function and Aggravating Alzheimer’s Pathology



Metformin: Potential Harm to Brain Cognitive Function and Aggravating Alzheimer’s Pathology

“Miracle Drug” Metformin Hits a Roadblock? Study in Nature Subjournal Warns of Potential Harm to Brain Cognitive Function, Aggravating Alzheimer’s Pathology—Particularly Alarming for This Group!

Metformin is a first-line drug for treating type 2 diabetes, acting by inhibiting the production of glucose in the liver to reduce blood sugar levels.  Globally, about 150 million people take Metformin, making it one of the most widely used oral hypoglycemic drugs.

The reason Metformin has been hailed as a “monthly must” is its effectiveness in lowering blood sugar levels. With ongoing scientific advancements, research on Metformin has continued, revealing over 20 effects, including cardiovascular protection, weight reduction/obesity management, improved lipid metabolism, reduced risk of certain tumors, and even improved Alzheimer’s disease (AD).

Previously, researchers observed a common phenomenon: the risk of developing Alzheimer’s disease is often higher in type 2 diabetes patients, speculating that the two diseases share a common pathogenic mechanism, “insulin resistance.”

As a potent insulin sensitizer, Metformin can benefit the body’s metabolism by activating AMP-dependent protein kinase (AMPK). Based on this, Metformin has become one of the “most competitive” candidate drugs for treating AD.

However, a recent study published in a Nature subjournal has delivered a shocker—long-term Metformin treatment may impair the cognitive function of individuals with AD.

Specifically, the efficacy of the “miracle drug” Metformin should be discussed according to the situation, as it has different effects on young and old individuals, especially those with AD.

In young mice, long-term Metformin treatment for 1-2 years can improve their attention, inhibitory control, and associative learning abilities. However, in older mice, prolonged use of Metformin can lead to impaired memory retention and discrimination learning abilities, especially in those with AD.

Metformin: Potential Harm to Brain Cognitive Function and Aggravating Alzheimer's Pathology

Researchers conducted experiments on two types of mice, including non-transgenic mice C57BL/6 (normal) and transgenic mice 3xTg-AD (AD), administering Metformin to them for almost their entire lifespan.

The dosage of Metformin was calculated based on the mice’s daily water intake (approximately 5mL/day), resulting in a dose of 300mg/kg/day, equivalent to the clinically used 2000mg/person/day for humans.

In young C57BL/6 mice, the “miracle drug” status of Metformin remained unchallenged. Under Metformin treatment, young mice showed enhanced attention, inhibitory control, and associative learning abilities.

Specifically, researchers used a five-choice serial reaction time task (5-CSRT) to test the mice’s attention. The results showed that under Metformin treatment, young mice exhibited higher response accuracy, lower premature responses, and higher persistence responses to correct stimuli. In other words, Metformin enhanced the executive function associated with the frontal lobe in young C57BL/6 mice.

At the same time, researchers also used the paired-associate learning (PAL) task to assess the mice’s temporal lobe-related learning and memory. It was found that there was a significant drug-time interaction in accuracy and correction trials, indicating that Metformin improved the mice’s learning performance. However, the above “improvement” was only present in middle-aged mice aged 12-14 months, not in older mice aged 17 months.

However, a reversal occurred! In older C57BL/6 mice over 19 months old, long-term Metformin treatment brought some health drawbacks—impaired visual discrimination and memory retention abilities in older mice.

Visual discrimination and reversal learning tests showed that 25-month-old mice treated with Metformin had impaired visual discrimination ability, but their reversal learning ability was comparable (indicating no difference in cognitive flexibility). At the same time, when researchers tested the mice with a retention memory task, they found that compared to the control group, those treated with Metformin exhibited impaired memory retention.

In individuals already suffering from Alzheimer’s disease, long-term Metformin treatment exacerbated the decline in cognitive abilities in AD mice.

It is well known that the “miracle drug” Metformin has the effect of prolonging life, a trend indeed reflected in 3xTg-AD mice. However, PAL testing showed that long-term Metformin treatment led to associative learning impairments in AD mice, exacerbating the decline in cognitive abilities.

Further exploration found the key to open the “Pandora’s box”—upregulation of hippocampal AMPKα1 subunits in AD mice. As mentioned earlier, AMPK dysfunction and changes in AMPK subunit expression can induce AD pathology; after taking Metformin, the expression of AMPKα1 in the mouse hippocampus significantly increased, leading to the occurrence of cognitive impairments.

At the same time, long-term Metformin treatment also increased levels of Aβ oligomers and Aβ plaques, significantly increasing p-tau levels at Ser356 and Thr231. These findings all demonstrate that long-term Metformin treatment exacerbates AD pathology.

In summary, Metformin is not suitable for treating Alzheimer’s disease, and long-term use may even lead to learning disabilities and worsen AD pathology in AD mice. However, there is no need to condemn it outright; the use of Metformin needs to be discussed in a nuanced manner—while it does improve cognition in young mice, prolonged use in older and AD mice can induce cognitive impairments and exacerbate AD pathology.

Of course, the above study is still at the animal experimental level, requiring further human trials for confirmation. However, this discovery also serves as a warning for clinical medication, especially in the use of Metformin in AD patients!

As the saying goes, “There is no perfect drug,” even the “miracle drug” Metformin has its drawbacks…

Metformin: Potential Harm to Brain Cognitive Function and Aggravating Alzheimer’s Pathology

References:

[1]Cho SY, Kim EW, Park SJ, Phillips BU, Jeong J, Kim H, Heath CJ, Kim D, Jang Y, López-Cruz L, Saksida LM, Bussey TJ, Lee DY, Kim E. Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer’s model mice. Transl Psychiatry. 2024 Jan 18;14(1):34. doi: 10.1038/s41398-024-02755-9. PMID: 38238285; PMCID: PMC10796941.

(source:internet, reference only)


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