Cancer Medication Improves Cognition in Alzheimer’s Mouse Model
Trametinib works by blocking the activity of the MEK 1 and MEK 2 proteins, activating nerve cell autophagy
Trametinib, an oral medication approved to treat certain cancers, improved cognition and neuronal health in a mouse model of Alzheimer’s disease, according to a new study.
Data suggest the treatment helped to clear toxic protein aggregates from nerve cells.
The study, “MEK1/2 inhibition rescues neurodegeneration by TFEB-mediated activation of autophagic lysosomal function in a model of Alzheimer’s Disease,” was published in Molecular Psychiatry.
The work was funded in part by Genuv, which is developing a formulation of trametinib called SNR1611 to treat Alzheimer’s and other neurological disorders. The study was also supported by the Korea Health Industry Development Institute.
“We are excited to share these extremely encouraging preclinical results. We believe we have demonstrated early proof of a new approach to neurodegenerative disease,” Sungho Han, PhD, founder and CEO of Genuv and co-author of the study, said in a company press release.
Trametinib works by blocking the activity of the proteins MEK 1 and MEK 2, which are involved in signaling pathways that help coordinate cellular survival processes. It’s approved to treat certain cancers under the trade name Mekinist, marketed by Novartis.
Here, scientists tested trametinib in 5XFAD mice, a mouse model of Alzheimer’s disease driven by a collection of disease-associated mutations.
“A therapeutic agent that could selectively inhibit the [MEK] pathway has not been evaluated in [Alzheimer’s] treatment,” the research team noted.
Initial tests confirmed the therapy could get into the mice’s brains when given orally and was reducing MEK signaling, as expected. Then, 5-month-old mice were treated with 0.1 mg/kg trametinib or an inactive solution once daily for 10 weeks and the researchers compared their performance on a number of cognitive measures.
In tests of short-term memory (Y-maze) and long-term memory (novel object recognition test), untreated 5XFAD mice showed marked impairments compared to non-Alzheimer’s mice. By contrast, 5XFAD mice given trametinib performed comparably to non-Alzheimer’s mice.
“These results demonstrate that orally administered trametinib improves cognitive dysfunctions in 5XFAD,” the researchers wrote.
Analyses of the mice’s hippocampuses, a brain region critical for memory, showed trametinib improved long-term potentiation (LTP) — a phenomenon where nerve cells that signal to each other often will form stronger synapses (connections), which is critical to memory formation. It also improved the health of dendrites and axons, the wire-like projections that nerve cells use to connect with each other.
“Trametinib administration ameliorated memory deficits and rectified synaptic dysfunction by improving LTP and increasing synaptic protein expression in 5XFAD mice,” the researchers wrote.
5XFAD mice treated with trametinib also showed a marked reduction in levels of amyloid-beta plaques — toxic clumps of protein characteristic of Alzheimer’s and thought to help drive the disease. Experiments using cells in dishes showed trametinib protected nerve cells against damage caused by amyloid-beta.
The scientists also demonstrated that trametinib activated autophagy in nerve cells. Derived from Greek words for “self-eating,” autophagy is a process wherein cells break down their own complex contents into simpler raw materials that can be reused. This process occurs in cellular structures called lysosomes.
The researchers showed that, by blocking MEK signaling, trametinib boosted the activity of a powerful autophagy-driving protein called TFEB. The increase in autophagy helped clear out the toxic amyloid-beta plaques, thus preventing damage to the nerve cells.
“We clearly showed that MEK inhibition by trametinib provides neuronal protection from [amyloid-beta] burden by increasing autophagic lysosomal activity through TFEB activation in models of AD [Alzheimer’s disease],” the scientists concluded. “Thus, therapeutic utility of MEK inhibition may have broad neuroprotective properties in other neurodegenerative diseases such as AD-related dementia and Parkinson’s disease where autophagic lysosomal activity plays a role.”
“We plan to continue our pre-clinical exploration of MEK 1/2 inhibitors,” Han said.