Diabetes Meds May Normalize Dementia-Related Changes in Brain Gene Expression

By Will Boggs MD

November 15, 2018

NEW YORK (Reuters Health) - Antidiabetic agents appear to normalize the aberrant expression of endothelial and insulin receptor signaling pathway (IRSP) genes in the parahippocampal gyrus of patients with Alzheimer disease (AD), researchers report.

"I found the prominence of the microvascular/endothelial cell abnormalities in AD the most interesting," said Dr. Vahram (Harry) Haroutunian from Icahn School of Medicine at Mount Sinai, in New York City.

"I think the fact that diabetes medications seem to improve the expression of these markers is very interesting, since it suggests the opportunity for new therapeutic avenues," he told Reuters Health by email.

Dr. Haroutunian and colleagues previously found that elderly people with type 2 diabetes treated with insulin plus other hypoglycemic agents had dramatically less AD neuropathology than otherwise similar persons without diabetes.

In the current study, they examined IRSP and endothelial cell markers in the parahippocampal gyri of 30 controls, 19 patients with AD and 34 patients with AD and diabetes treated with antidiabetic medications.

Compared with controls, patients with AD had significantly altered mRNA expression of 12 of the 18 endothelial cell and IRSP-associated genes in whole-tissue homogenates of the parahippocampal gyrus (six of 12 remained significant after correction for false-discovery rate).

In contrast, only four of these 12 genes had significantly altered expression in patients with AD who had a history of receiving antidiabetic treatment (one after correction).

Similarly, compared with controls, five endothelial and IRSP-related genes were abnormally expressed in endothelial cells of the parahippocampal gyrus in AD patients. But only one such gene was abnormally expressed in the endothelial cells of AD patients treated with antidiabetic agents, the researchers report in PLoS ONE, online November 1.

As for non-IRSP and/or non-endothelial cell mRNA expression, eight of the 23 mRNAs studied differed significantly between AD patients and controls. These included mRNAs encoding proteins associated with synaptic function, astrocytes, cell adhesion and immune/inflammation responses.

Only three of these markers showed different mRNA expression in patients treated with antidiabetic medication.

"Whether these endothelial and IRSP abnormalities contribute to the genesis of AD neuropathology or whether they result from other neuropathological changes cannot be determined in postmortem studies," the researchers note.

They caution, "The fact that no brains from AD plus diabetes donors that had not been treated with antidiabetic agents were included in this study is a distinct weakness and detracts from interpretative power."

"We don't know nearly enough about the interplay of the myriad of the systems within the brain, including the interplay between endothelial cells, astrocytes, and neurons," Dr. Haroutunian said. "I suspect that learning how these systems act as functional units is going to be critical to the development of effective therapeutics."

Dr. David M. Holtzman of Washington University School of Medicine, in St. Louis, Missouri, who has studied changes in insulin and insulin signaling in AD but was not involved in the new work, told Reuters Health by email, "The implication (of the findings) is that it may be possible that treatment of people with antidiabetic medications may be helpful cognitively but also protective against dementia due to Alzheimer’s. This would have to be directly tested to prove this, but this is an implication of the findings."

SOURCE: https://bit.ly/2OHjqXE

PLoS ONE 2018.