John K. Young

Does a brain dysfunction cause diabetes mellitus?

One unexplained feature of Alzheimer’s disease (AD) is that the lateral entorhinal cortex undergoes neurodegeneration before other brain areas. However, this brain region does not have elevated levels of amyloid peptides in comparison with undamaged regions. What is the cause of this special vulnerability of the entorhinal cortex? One special feature of the lateral entorhinal cortex is that it projects to newborn neurons that have undergone adult neurogenesis in the dentate gyrus of the hippocampus. Neurogenesis is abnormal in human AD brains, and modulation of neurogenesis in experimental animals influences the course of AD. This complex process of neurogenesis may expose axon terminals originating from neurons of the entorhinal cortex to a unique combination of molecules that can enhance toxic effects of amyloid. Retrograde degeneration of neurons with axons terminating in the dentate gyrus provides a likely explanation for the spatial patterns of neuronal cell death seen in AD. Specialized astrocytes in the dentate gyrus participate in adult neurogenesis and produce fatty acid binding protein7 (FABP7). These FABP7+ cells undergo an aging-related mitochondrial pathology that likely impairs their functions. This age-related abnormality may contribute to the impairment in neurogenesis seen in aging and Alzheimer’s disease. Also, a compromised function of these astrocytes likely results in local elevations of palmitic acid, iron, copper, and glucose, which all enhance the toxicity of amyloid peptides. Treatments that modulate neurogenesis or diminish the production of these toxic substances may prove more successful than treatments that are solely aimed at reducing the amyloid burden alone.

Recent research has determined that newborn neurons in the dentate gyrus of the hippocampus of the macaque are frequently adjacent to astrocytes immunoreactive for fatty acid binding protein‐7 (FABP7). To investigate if a similar relationship between FABP7‐positive (FABP7+) astrocytes and proliferating cells exists in the rodent brain, sections of brains from juvenile rats were stained by immunohistochemistry to demonstrate newborn cells (antibody to Ki67 protein) and FABP7+ astrocytes. In rat brains, FABP7+ astrocytes were particularly abundant in the dentate gyrus of the hippocampus and were frequently close to dividing cells immunoreactive for Ki67 protein. FABP7+ astrocytes were also present in the olfactory bulbs, arcuate nucleus of the hypothalamus, and in the dorsal medulla subjacent to the area postrema, sites where more modest numbers of newborn neurons can also be found. These data suggest that regional accumulations of FABP7+ astrocytes may represent reservoirs of cells having the potential for neurogenesis. Because FABP7+ astrocytes are particularly abundant in the hippocampus, and since the gene for FABP7 has been linked to Alzheimer's disease, age‐related changes in FABP7+ astrocytes (mitochondrial degeneration) may be relevant to age‐associated disorders of the hippocampus.

A central neuronal network that regulates respiration may include hypothalamic neurons that produce orexin, a peptide that influences sleep and arousal. In these experiments, we investigated 1) projections of orexin-containing neurons to the pre-Bötzinger region of the rostral ventrolateral medulla that regulates rhythmic breathing and to phrenic motoneurons that innervate the diaphragm; 2) the presence of orexin A receptors in the pre-Bötzinger region and in phrenic motoneurons; and 3) physiological effects of orexin administered into the pre-Bötzinger region and phrenic nuclei at the C₃–C₄ levels. We found orexin-containing fibers within the pre-Bötzinger complex. However, only 0.5% of orexin-containing neurons projected to the pre-Bötzinger region, whereas 2.9% of orexin-containing neurons innervated the phrenic nucleus. Neurons of the pre-Bötzinger region and phrenic nucleus stained for orexin receptors, and activation of orexin receptors by microperfusion of orexin in either site produced a dose-dependent, significant ( P < 0.05) increase in diaphragm electromyographic activity. These data indicate that orexin regulates respiratory activity and may have a role in the pathophysiology of sleep-related respiratory disorders.

A specialized subtype of astrocyte, the Gomori-positive (GP) astrocyte, is unusually abundant and prominent in the arcuate nucleus of the hypothalamus. GP astro-cytes possess cytoplasmic granules derived from degenerating mitochondria. GP granules are highly stained by Gomori's chrome alum hematoxylin stain, by the Perl's reaction for iron, or by toluidine blue. The source of the oxidative stress causing mitochondrial damage in GP astrocytes is uncertain, but such damage could arise from the oxidative metabolism of glucose transported into astrocytes by high-capacity GLUT2 glucose transporters. In accord with this hypothesis, the reported anatomical distribution of astrocytes staining positively for GLUT2 glucose transporters closely matches that of GP astrocytes. To examine whether or not these two staining procedures detect the same population of astrocytes, immunocytochemistry was performed on semithin sections to detect GLUT2 protein and sections were then stained with toluidine blue to detect GP granules. It was determined that GP astrocytes are frequently immunoreactive for the GLUT2 transporter protein. These data support the possibility that GP astrocytes may have an important influence upon the reactivity of the hypothalamus to glucose and that a specialized glucose metabolism may in part underlie the development of mitochondrial abnormalities in hypothalamic GP astrocytes.