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PLoS One. 2018 Nov 1;13(11):e0206547. doi: 10.1371/journal.pone.0206547. eCollection 2018.

Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents.

Author information

1
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
2
Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
3
Mental Illness Research, Education and Clinical Center, J.J. Peters VA Medical Center, Bronx, New York, United States of America.
4
The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Aviv, Israel.
5
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
6
Division of Neurology, J.J. Peters VA Medical Center, Bronx, New York, United States of America.
7
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
8
General Medical Research Service, J.J. Peters VA Medical Center, Bronx, New York, United States of America.

Abstract

A large body of literature links risk of cognitive decline, mild cognitive impairment (MCI) and dementia with Type 2 Diabetes (T2D) or pre-diabetes. Accumulating evidence implicates a close relationship between the brain insulin receptor signaling pathway (IRSP) and the accumulation of amyloid beta and hyperphosphorylated and conformationally abnormal tau. We showed previously that the neuropathological features of Alzheimer's disease (AD were reduced in patients with diabetes who were treated with insulin and oral antidiabetic medications. To understand better the neurobiological substrates of T2D and T2D medications in AD, we examined IRSP and endothelial cell markers in the parahippocampal gyrus of controls (N = 30), of persons with AD (N = 19), and of persons with AD and T2D, who, in turn, had been treated with anti-diabetic drugs (insulin and or oral agents; N = 34). We studied the gene expression of selected members of the IRSP and selective endothelial cell markers in bulk postmortem tissue from the parahippocampal gyrus and in endothelial cell enriched isolates from the same brain region. The results indicated that there are considerable abnormalities and reductions in gene expression (bulk tissue homogenates and endothelial cell isolates) in the parahippocampal gyri of persons with AD that map directly to genes associated with the microvasculature and the IRSP. Our results also showed that the numbers of abnormally expressed microvasculature and IRSP associated genes in diabetic AD donors who had been treated with anti-diabetic agents were reduced significantly. These findings suggest that anti-diabetic treatments may reduce or normalize compromised microvascular and IRSP functions in AD.

Conflict of interest statement

The authors have declared that no competing interests exist.

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