Trametinib: Potential therapeutic game-changer for Alzheimer's disease

In a recent study published in Nature's Experimental & Molecular Medicine, researchers developed the ATRIVIEW® platform to screen for molecules that promote differentiation of adult murine neural stem cells (NSCs).

Study: Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer’s disease. Image Credit: Andrii Vodolazhskyi/Shutterstock.com

Background

Alzheimer's disease (AD) is a brain ailment that causes cognitive impairment and loss of memory due to the death of cortical and hippocampal neurons.

Although the pathogenic pathways of Alzheimer's disease are not entirely understood, amyloid plaques and hyperphosphorylated tau protein tangles disrupt neuronal networks via autophagic-lysosomal failure, synaptic loss, mitochondrial dysregulation, and neuroinflammation.

Despite discovering Alzheimer's disease medicines to remove these tau tangles and plaques, disease-modifying drugs have proven ineffective. Improving adult neurogenesis in the brain might be a possible Alzheimer's disease treatment method.

About the study

In the present study, researchers investigated whether enhancing adult neurogenesis from endogenous NSCs could restore neuronal network integrity in affected brain regions of AD patients.

B6SJL-Tg (5XFAD) and wild-type (WT) murine animals were used for the analysis. The mice received 0.1 mg per kg of trametinib for 1.0 months, 1.5 months, and 2.5 months through oral gavage once daily. In addition, intraperitoneal temozolomide (TMZ, 25 mg/kg) injections were provided to the animals thrice weekly for six weeks.

Murine brain specimens were subjected to immunohistochemical and biochemical analyses and examined using laser-scanning confocal microscopy.

In addition, Western blot analysis, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and whole-cell ribonucleic acid (RNA) sequencing were performed. Gene expression was assessed by performing differential gene expression analysis and gene ontology analysis.

Behavior tests were performed, including the novel object recognition test and the fear conditioning test. The researchers isolated primary NSCs from the subventricular zone (SVZ) of C57BL/6 mice (aged eight weeks) or 5XFAD mice (aged eight months), and a neurosphere culture was performed.

Human-induced pluripotent stem cells (iPSC) were obtained from an AD patient (female, aged 33 years) and a healthy individual (female, aged 22 years).

Neural stem cells were differentiated from iPSCs. NSCs obtained from Tg2576 mice were used to screen for drugs that could enhance adult NSC differentiation using the ATRIVIEW® platform.

To determine whether the mitogen-activated protein kinase (MEK)/extracellular signal-related kinase (ERK) pathway was activated in NSCs of AD model mice with amyloid beta (Aβ) plaque phenotypes, the team measured the phosphorylated ERK (pERK, the downstream substrate of MEK1/2) level in the brains of WT and 5XFAD AD model mice.

Results

The researchers screened 994 small compounds from a Food and Drug Administration (FDA)-approved medication library using NSCs generated from the Tg2576 Alzheimer's disease murine model to find small molecules stimulating neuronal development.

Using fluorescent immunocytochemical analysis to examine the amount of Tuj1 (neuron-specific class III β-tubulin) expression, 48 substances were shown to enhance neuronal differentiation (a minimum of a two-fold elevation compared to controls).

SNR1611 (trametinib), a selective inhibitor of MEK-1/2 and FDA-authorized antineoplastic medication, was the most powerful hit from an FDA-approved drug library. Trametinib stimulated the neuronal development of adult neural stem cells in the Alzheimer's disease murine model using the phenotype-based screening tool ATRIVIEW®.

In vitro, trametinib elevated levels of the P15INK4b (promoting cell cycle arrest) and the proneuronal factor neurogenin 2 (Neurog2), revealing a mechanism by which MEK1/2 inhibition drives neuronal differentiation.

Trametinib, which inhibits MEK/ERK activity, boosted neurogenesis of neural stem cells in the hippocampus, cortex, subventricular zone (SVZ), and dentate gyrus (DG) in the B6SJL-Tg AD mouse model.

Trametinib also produced functional restoration of AD pathogenesis in the AD murine model by repairing the structure and quantity of brain neurons and recovering cognitive skills.

Trametinib also stimulated the neurogenic development of NSCs produced from Alzheimer's disease patient-induced pluripotent stem cells, indicating its therapeutic potential.

Trametinib therapy changed the morphology of NSC into neuron-like cells. Trametinib prevented proliferation [based on proliferating cell nuclear antigen (PCNA) levels] and induced neuronal differentiation (Tuj1 levels) but not astrocytic differentiation [based on glial fibrillary acidic protein (GFAP) levels] of adult neural stem cells obtained from C57B/L6 murine animals in the culture medium with growth factors (20 ng/ml of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF)].

Trametinib administration (for 2.50 to five-month-old 5XFAD animals) decreased the level of pERKs in both locations, demonstrating that trametinib penetrated the brains of 5XFAD mice and suppressed MEK-ERK signaling.

Further, trametinib increased the expression of neurogenin 2 (Ngn2) target genes such as Ebf-1, Ebf-3, Nescient helix loop helix 2 (Nhlh-2), Iroquois Homeobox 3 (Irx-3), Irx5, SRY-Box Transcription Factor 14 (Sox-14), E-Cadherin (Cdh1), and TEA domain transcription factor 4 (Tead-4).

Trametinib also lowered the amounts of amyloid beta protein, active caspase-3, and cleaved poly (ADP-ribose) polymerase (PARP).

Other MEK1/2 inhibitors (PD184352, AZD8330, PD318088, Refametinib, and AS703026) stimulated neuronal differentiation in embryonic NSCs, demonstrating that MEK1/2 inhibition promoted neuronal differentiation.

Based on the study findings, restoring endogenous adult neurogenesis with trametinib via MEK/ERK inhibition could be a potential therapeutic approach to Alzheimer's disease.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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