Showing papers by "Jacob Raber published in 2010"

Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children.

Abstract: Apolipoprotein E4 (apoE4) and female sex are risk factors for developing Alzheimer's disease. It is unclear whether apoE4 contributes to behavioral function at younger ages. Standard neuropsychological assessments [intelligence quotient (IQ), attention, and executive function] and a test developed in this laboratory (Memory Island test of spatial learning and memory) were used to determine whether E4 and sex affect neuropsychological performance in healthy primary school children (age 7–10). A medical history was also obtained from the mother to determine whether negative birth outcomes were associated with apoE4. Mothers of apoE4+ children were more likely to report that their newborn was placed in an intensive care unit. A sex difference in birth weight was noted among apoE4− (males > females), but not apoE4+, offspring. Conversely, among apoE4+, but not apoE4− children, there was a sex difference in the Wechsler Abbreviated Scale of Intelligence (WASI) vocabulary score favoring boys. ApoE4− girls had better visual recall than apoE4+ girls or apoE4− boys on the Family Pictures test. Finally, apoE4+, unlike apoE4−, children did not show spatial memory retention during the Memory Island probe trial. Thus, apoE4 may affect neurobehavioral performance, particularly spatial memory, and antenatal health decades before any clinical expression of neurodegenerative processes.

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Abstract: Loss of synaptic integrity in the hippocampus and prefrontal cortex (PFC) may play an integral role in age-related cognitive decline. Previously, we showed age-related increases in the dendritic marker microtubule associated protein 2 (MAP-2) and the synaptic marker synaptophysin (SYN) in mice. Similarly, apolipoprotein E (apoE), involved in lipid transport and metabolism, and glial fibrillary acidic protein (GFAP), a glia specific marker, increase with age in rodents. In this study, we assessed whether these four proteins show similar age-related changes in a nonhuman primate, the rhesus macaque. Free-floating sections from the PFC and hippocampus from adult, middle-aged, and aged rhesus macaques were immunohistochemically labeled for MAP-2, SYN, apoE, and GFAP. Protein levels were measured as area occupied by fluorescence using confocal microscopy as well as by Western blot. In the PFC and hippocampus of adult and middle-aged animals, the levels of SYN, apoE, and GFAP immunoreactivity were comparable but there was a trend towards higher MAP-2 levels in middle-aged than adult animals. There was significantly less SYN and more MAP-2, apoE, and GFAP immunoreactivity in the PFC and hippocampus of aged animals compared to adult or middle-aged animals. Thus, the age-related changes in MAP-2, apoE, and GFAP levels were similar to those previously observed in rodents. On the other hand, the age-related changes in SYN levels were not, but were similar to those previously observed in the aging human brain. Taken together, these data emphasize the value of the rhesus macaque as a pragmatic translational model for human brain aging.

Long-term effects of methamphetamine exposure on cognitive function and muscarinic acetylcholine receptor levels in mice.

Abstract: Exposure to methamphetamine during brain development impairs cognition in humans and rodents. In mice, these impairments are greater in females than males. Genetic factors, such as apolipoprotein E genotype, may modulate the cognitive effects of methamphetamine. Methamphetamine-induced alterations in the brain acetylcholine system may contribute to the cognitive effects of methamphetamine and may also be modulated by apolipoprotein E isoform. We assessed the long-term effects of methamphetamine exposure during brain development on cognitive function and muscarinic acetylcholine receptors in mice, and whether apolipoprotein E isoform modulates these effects. Mice expressing human apolipoprotein E3 or E4 were exposed to methamphetamine (5 mg/kg) or saline once a day from postnatal day 11-20 and behaviorally tested in adulthood. Muscarinic acetylcholine receptor binding was measured in the hippocampus and cortex. Methamphetamine exposure impaired novel location recognition in female, but not male, mice. Methamphetamine-exposed male and female mice showed impaired novel object recognition and increased number of muscarinic acetylcholine receptors in the hippocampus. The cognitive and cholinergic effects of methamphetamine were similar in apolipoprotein E3 and E4 mice. Thus, the cholinergic system, but not apolipoprotein E isoform, might play an important role in the long-term methamphetamine-induced cognitive deficits in adulthood.

Unintended effects of cranial irradiation on cognitive function.

Abstract: This review summarizes some of the topics discussed at the 28th Annual Symposium of the Society of Toxicologic Pathology. The symposium was held in Washington, DC, in 2009 and dealt with unintended adverse events associated with cranial irradiation as part of cancer therapy. We will discuss the importance of considering genetic susceptibility and sex differences in susceptibility to develop these adverse events. Further, we will discuss potential mechanisms contributing to these events, including alterations in neurogenesis and increased oxidative stress following irradiation and potential alterations in synaptic and dendritic markers.

Effects of ε4 on Object Recognition in the Non-Demented Elderly

Abstract: Previously we reported that Apolipoprotein E (ApoE) e4 negatively affects performance in the novel-image-novel- location (NINL) object recognition test in healthy non-demented elderly human study participants. In this study, the participants were invited to return for testing sessions 6 and 18 months after the baseline session. Using a longitudinal study design, effects of e4 on NINL test performance were assessed in study “dropouts”, participants that did not return for the second and/or third session(s), and “finishers”, participants that returned for all sessions. There were effects of e4 on dropout rates and NINL total scores as well as sub-scores in both dropouts and finishers. NINL total score was a predictor of e4 participant dropout. Compared to non-e4 dropouts, e4 dropouts had lower NINL scores. In contrast, e4 finishers had higher NINL scores than non-e4 finishers. Thus, the NINL test could be a valuable tool in detecting preclinical signs of age-related cognitive impairments, particularly those associated with e4 risk.

Isoform-dependent effects of apoE on doublecortin-positive cells and microtubule-associated protein 2 immunoreactivity following 137Cs irradiation

Abstract: Previously we found apoE isoform-dependent effects of 137Cs irradiation on cognitive function of female mice 3 months following irradiation. Alterations in the number of immature neurons and in the levels of the dendritic marker microtubule-associated protein 2 (MAP-2) might contribute to the cognitive changes following irradiation. Therefore, in the present study we determined if, following 137Cs irradiation, there are apoE isoform-dependent effects on loss of doublecortin-positive neuroprogenitor cells or MAP-2 immumonoreactivity. In the dentate gyrus, CA1 and CA3 regions of the hippocampus, enthorhinal and sensorimotor cortex, and central and basolateral nuclei of the amygdala of apoE3 female mice, MAP-2 immunoreactivity increased 3 months following 137Cs irradiation. In addition, at 8 h following irradiation, the number of doublecortin-positive cells was higher in apoE3 than apoE2 or apoE4 mice. Together, these data indicate that brains of apoE3 mice respond differently to 137Cs irradiation than those of apoE2 or apoE4 mice.

Isoform-dependent effects of apoE on doublecortin-positive cells and microtubule-associated protein 2 immunoreactivity following

Abstract: Previously we found apoE isoform-dependent effects of 137 Cs irradiation on cognitive function of female mice 3 months following irradiation. Alterations in the number of immature neurons and in the levels of the dendritic marker microtubule-associated protein 2 (MAP- 2) might contribute to the cognitive changes following irradiation. Therefore, in the present study we determined if, following 137 Cs irradiation, there are apoE isoform- dependent effects on loss of doublecortin-positive neuro- progenitor cells or MAP-2 immumonoreactivity. In the dentate gyrus, CA1 and CA3 regions of the hippocampus, enthorhinal and sensorimotor cortex, and central and basolateral nuclei of the amygdala of apoE3 female mice, MAP-2 immunoreactivity increased 3 months following 137 Cs irradiation. In addition, at 8 h following irradiation, the number of doublecortin-positive cells was higher in apoE3 than apoE2 or apoE4 mice. Together, these data indicate that brains of apoE3 mice respond differently to 137 Cs irradiation than those of apoE2 or apoE4 mice.