In a recent study published in Aging Cell, researchers found similarities between glioblastoma and Alzheimer’s disease patients in their gene expression and protein profiles [1].
Brain tumors and neurocognitive dysfunction
The majority of patients with brain tumors develop irreversible, progressive neurocognitive dysfunction, sometimes long after their treatment [2-4]. It reduces their quality of life and, in some cases, can lead to dementia [5, 6].
Radiotherapy and chemotherapy play a major role in the development of this neurocognitive dysfunction [7, 8]. Therefore, the authors of this paper investigated the brains of patients with glioblastoma, a brain cancer, on a molecular level and noticed interesting similarities to brains with Alzheimer’s disease.
Gene expression similarities
The authors obtained postmortem brain samples from glioblastoma patients. They compared normal-appearing non-tumor brain tissue from glioblastoma patients who received cancer treatment to the tissue from the same brain regions of Alzheimer’s disease patients who didn’t have brain tumors.
The researchers performed a transcriptomic analysis, determining which genes in these tissues were active and at what levels. The three samples from glioblastoma patients included two samples from regions close to the tumor and one further away. The control samples from people without cancer came from the same regions and people of similar age.
The researchers identified over 1200 differentially expressed genes in each region closer to the tumor and 301 differentially expressed genes in the further region. Reduction in gene expression changes in the regions further from the tumor suggests that these changes are associated with the tumor environment or are induced by radiation therapy.
When the researchers compared all (near and far) normal-appearing brain tissue samples from glioblastoma patients to control samples, they found the gene expression differed between samples. The analysis found 601 upregulated genes and 596 downregulated genes when patients were compared with controls.
Next, the authors performed gene ontology analysis, in which genes are grouped based on the biological processes in which they are involved, their molecular functions, and where in the cell they are located. They noted that the most common terms in the upregulated genes group were related to inflammation and regulation of inflammatory response. The most common terms in the downregulated genes were related to oxidative phosphorylation and proton transmembrane transport.
The researchers aimed to understand whether changes in the glioblastoma patients’ brain tissues resemble any other disease, comparing their results with previously published data. They found that the 140 upregulated and 156 downregulated genes identified in the glioblastoma patients overlap with genes identified in an Alzheimer’s study [9] but not with other analyzed neurodegenerative diseases.
Protein quantity similarities
The analysis of the gene expression data also pointed to mitochondrial dysfunction in glioblastoma patients’ brains. To further investigate this, the researchers measured mitochondrial protein levels. They didn’t observe changes in total levels, but one protein, called OPA1, was reduced in normal-appearing brain tissues from glioblastoma patients.
OPA1 is responsible for, among other processes, mitochondria fusion, mitochondrial stability, and energy output. Those results align with previous gene expression analyses that suggested reduced oxidative phosphorylation.
The authors also analyzed levels of several other proteins and compared them to those of the Alzheimer’s patients. This analysis showed increased levels of oxidative stress and DNA damage in normal-appearing glioblastoma patients’ brain tissues, similar to that of Alzheimer’s patients.
Glioblastoma patients’ normal-appearing brain tissue also had increased levels of lysosomal lipofuscin compared to controls. The accumulation of this protein is a hallmark of aging, age-related neurodegeneration, and Alzheimer’s disease [10].
Similarly, levels of tau protein, which is hyperphosphorylated and forms aggregates in Alzheimer’s disease [11], were significantly higher in normal-appearing brain tissue from glioblastoma patients. However, the researchers didn’t observe a significant increase in amyloid-β42, a known hallmark of Alzheimer’s disease.
The authors summarized that “these data suggest that the brain of GBM patients contains hallmarks of accelerated aging and AD-like neuropathological features.”
The need for better treatment
The authors admit they cannot exclude the possibility that these glioblastoma patients had pre-existing Alzheimer’s disease in their brains. However, the gradient in gene expression changes between near and far brain regions suggests that these changes are tumor or tumor-therapy dependent.
The researchers suggest that radiotherapy and chemotherapy play a role in those changes, as previous work in rodents has shown irradiation leading to “behavioral and cognitive changes, and neuroinflammation” [4, 12, 13].
The authors believe that research into how the human brain responds to cancer and the associated treatment is essential to develop interventions that can help patients and improve their quality of life.
Literature
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