Identifying regulators of brain reserve and neuropathological changes in cognitive and mood disorders
Kao, Patricia F
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Neurodegenerative and neuropsychiatric diseases may share molecular regulators implicated in their pathogeneses as the expression of brain derived neurotrophic factor (BDNF) is altered in both. BDNF and its receptor Tyrosine kinase B (TrkB) may influence brain reserve- the ability of the brain to tolerate pathological changes such as those seen in Alzheimer's Disease (AD) before manifesting clinical signs and symptoms. I investigated whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of AD and whether that response depends on an upregulation of the BDNF pathway. I observed increased neuronal TrkB expression associated with early AD pathology in cognitively intact Framingham Heart Study subjects when compared to individuals with no neurofibrillary tangles. As BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, I also examined the expression of actin capping protein beta 2 (Capzb2), a marker of actin cytoskeleton reorganization. My data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. An extensive search for neuropathological changes in BD revealed reduced number of glial cells in the anterior cingulate cortex (BA24). A reduced number of astrocytes and oligodendrocytes is potentially detrimental for neuronal homeostasis. In examining mRNA expression of genes implicated in neuronal protection, BDNF and TrkB, in pyramidal neurons and glia in BA24, I did not find significant differences between BD patients and controls. Because microRNAs (miRNAs) regulate many genes involved in brain functions altered in BD and schizophrenia (SZ), I compared miRNA expression in exosomal extractions from prefrontal cortices of BD, SZ, and controls. Exosomes are secretory/signaling microvesicles that contain miRNA. I found specific miRNAs from exosome-enriched pellets of the prefrontal cortex of cases with neuropsychiatric disorders to be deregulated as compared to controls: miR-29c in BD, and miR-497 in SZ. In BA24 of BD patients, I found miR-149 to be deregulated. These findings may help explain the previously reported neuropathology of BD.
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