Characterization of the Early CNS Stress Biomarkers and Profiles Associated with Neuropsychiatric Diseases

X.      R. Lowe; A.      J. Wyrobek

doi:10.2174/138920212802510448

Abstract

Neuropsychiatric disorders (including dementia) have high personal, family, and social costs. Although many neuropsychiatric disorders share common patterns of symptoms and treatments, there are no validated biomarkers that define the underlying molecular mechanisms in the central nervous system (CNS). We hypothesize that there are early and common molecular changes in the CNS that will serve as sensitive indicators of CNS molecular stress and that will be predictive of neuropathological changes resulted in increasing the risk for neuropsychiatric diseases. Using the rodent model, we showed that systemic exposure to three diverse CNS stressors with different mechanisms of action (ketamine, low-dose and high-dose ionizing radiation, interferon-α) induced the expression of troponin T1 (Tnnt 1) within hours in adult mouse brain tissue. Tnnt 1 expression was induced in neuronal (not glial) cells, the hippocampal zone of neurogenesis, cerebral cortex, amygdale, and choroid plexus, which are important CNS locations in behavior and mental health. We also identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue for hours after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer’s disease. Our studies provide new molecular information on shared mechanisms and expression profiles of diverse neuropsychiatric disorders. This knowledge will be fundamental for developing molecular signatures of early CNS stress biomarker for early diagnosis and treatment of neuropsychiatric diseases.

Keywords: Early CNS stress biomarker, Interferon, Radiation, Low-dose, Ketamine, Microarray, Neuropsychiatric diseases, RNA in situ hybridization, Tnnt1, cerebral cortex, Alzheimer’s disease