Faculty Bibliography

Background: Neurotrophin signaling of cholinergic basal forebrain (CBF) neurons is critical for survival and plasticity. Microaspiration of identified CBF neurons from postmortem human brain revealed a shift in balance of neurotrophin receptors toward cell death pathways during the progression of Alzheimer's disease (AD). Methods: In this study transcriptomic data from mouse basal forebrain cholinergic neurons (BFCNs; NCBI GEO GSE13379) were used to derive parameters for a deterministic kinetic model of the nerve growth factor (NGF) signaling pathway from Reactome, with TrkB receptor mechanisms added. This method is called Transcriptome-To-Reactome (TTR)-. The biosimulation was performed using COPASI software and included 11 compartments 435 species, and 263 reactions; 245 genes were used to determine initial values of species and kinetic values of reactions. The mouse BFCN model was considered baseline and a biosimulation was run with two doses of NGF, 500 m M and 10 mM, delivered as a bolus and for a 10 and 240 second duration, respectively. This approach tested selectively for p75 NTR and TrkA receptor mediated mechanisms. A second biosimulation test used a combination of 25 mM brain derived neurotrophic factor (BDNF) and 10 m M NGF as a continuous exposure for 60 min duration; this approach evaluated stimulation of p75 NTR TrkA, and TrkB. Based on the human microarray results demonstrating downregulation of TrkA (50%) and TrkB (60%), the corresponding parameters in the TTR biosimulation were decreased by the same amount. Results: Baseline results were validated from published literature on neuronal calcium levels mediated via the phospholipase C-g and inositol- 3-phosphate pathway at both bolus doses of NGF alone. With the corresponding parameters decreased in the TTR biosimulation, Figure 1: A) The reaction flux for c-RAF1 phosphorylation of MEK1 was delayed to peak value by 1.5 min from exposure, but the peak value was increased to 5 times the baseline value; B) Moreover, a slight shift t!

Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of Alzheimer's disease (AD). Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF with a rate of production by far exceeding that of cortical neurons. Exposure of these cells to amyloid beta (Ab), results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Ab40 into the carotid resulted in a disruption of endothelial cells, which was not observed with Ab42. Plasma Ab40 levels have also been associated with white matter hyperintense lesions (WMHI) on MRI scans in AD, an effect that may be mediated by the toxic effects of soluble Ab40 on small cerebral blood vessels and endothelial cells. Therefore, we hypothesized that concentrations of plasma Ab40, but not Ab42, would have a negative effect on plasma BDNF and on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, we examined BDNF and Ab levels in plasma from 119 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Of these, 88 subjects also had BDNF in plasma determined. Results: Consistent with our prediction, Ab40 was inversely correlated with BDNF concentrations (P <.001), whereas Ab42 was independent (P = .231). Fractional anisotropy (FA; a measure of white matter integrity in DTI) was also inversely correlated with Ab40 (P = .001) and so was performance in delayed recall (P = .029). Conclusions: In cognitively intact individuals, circulating Ab40 results in reduction in plasma BDNF, white matter integrity (FA), and memory performance. As such, it may have prognostic significance

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression as well as neuropsychiatric and neurodegenerative disorders. Recent studies show a role of BDNF in energy metabolism and body weight regulation. We examined BDNF levels in plasma and cerebrospinal fluid (CSF) samples from age matched elderly depressed and control subjects. Also, the association of BDNF levels with age, gender, body weight, body mass index (BMI), and cognitive performance was evaluated. We did not find any significant differences in plasma and CSF BDNF levels between depressed and control subjects. Plasma BDNF levels were negatively correlated with age (but not with BMI and body weight), when analyses were performed including both depressed and control subjects. A significant reduction in plasma BDNF levels was observed in females as compared to male subjects, and the change in BDNF levels were significantly and positively related to body weight in females. Furthermore, significant increases in Total Recall and Delayed Recall values were found in females as compared to males. In conclusion, the lower BDNF levels observed in females suggest that changes in peripheral BDNF levels are likely secondary to an altered energy balance. However, further studies using larger sample size are warranted.

Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of depression. Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF within the brain. Exposure of these cells to amyloid beta (Abeta), which may play a role in the pathophysiology of late-life depression, results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Abeta40 into the carotid artery resulted in a disruption of endothelial cells, which was not observed with Abeta42 infusion. Therefore, we hypothesized that concentrations of plasma Abeta40, but not Abeta42, would have a negative effect on plasma BDNF levels. Methods: We examined BDNF and Abeta levels in plasma via immunoblotting and ELISA assays, respectively, from 88 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. As these subjects were originally recruited for a study on major depressive disorder (MDD), 45 had MDD and 43 were age-matched controls. Results: Consistent with our prediction, Abeta40 levels were inversely correlated with BDNF concentrations (p<.001), whereas Abeta42 levels were independent of BDNF expression (p=.231). This pattern was similar when MDD and control subjects were analyzed separately. Discussion: Our results are consistent with the hypothesis that cerebral endothelial cells are a contributing source of peripheral BDNF and that their disruption by circulating Abeta40 results in reduction in BDNF. However, these preliminary findings need confirmation, and the mechanisms for our observation, including Abeta40-induced cerebral endothelial cell dysfunction, will have to be clarified

This study was designed to understand molecular and cellular mechanisms underlying aggressive behaviors in mice exposed to repeated interactions in their homecage with conspecifics. A resident-intruder procedure was employed whereby two males were allowed to interact for 10 min trials, and aggressive and/or submissive behaviors (e.g., degree of attacking, biting, chasing, grooming, rearing, or upright posture) were assessed. Following 10 days of behavioral trials, brains were removed and dissected into specific regions including the cerebellum, frontal cortex, hippocampus, midbrain, pons, and striatum. Gene expression analysis was performed using real-time quantitative polymerase-chain reaction (qPCR) for catechol-O-methyltransferase (COMT) and tyrosine hydroxylase (TH). Compared to naive control mice, significant up regulation of COMT expression of residents was observed in the cerebellum, frontal cortex, hippocampus, midbrain, and striatum; in all of these brain regions the COMT expression of residents was also significantly higher than that of intruders. The intruders also had a significant down regulation (compared to naive control mice) within the hippocampus, indicating a selective decrease in COMT expression in the hippocampus of submissive subjects. Immunoblot analysis confirmed COMT up regulation in the midbrain and hippocampus of residents and down regulation in intruders. qPCR analysis of TH expression indicated significant up regulation in the midbrain of residents and concomitant down regulation in intruders. These findings implicate regionally- and behaviorally-specific regulation of COMT and TH expression in aggressive and submissive behaviors. Additional molecular and cellular characterization of COMT, TH, and other potential targets is warranted within this animal model of aggression

The higher incidence rate of Alzheimer's disease (AD) in elderly women indicates that gender plays a role in AD pathogenesis. Evidence from clinical and pharmacologic studies, neuropathological examinations, and models of hormone replacement therapy suggest that cholinergic basal forebrain (CBF) cortical projection neurons within the nucleus basalis (NB), which mediate memory and attention and degenerate in AD, may be preferentially vulnerable in elderly women compared to men. CBF neurons depend on nerve growth factor (NGF) and their cognate receptors (trkA and p75(NTR)) for their survival and maintenance. We recently demonstrated a shift in the balance of NGF and its receptors toward cell death mechanisms during the progression of AD. To address whether gender affects NGF signaling system expression within the CBF, we used single cell RNA amplification and custom microarray technologies to compare gene expression profiles of single cholinergic NB neurons in tissue specimens from male and female members of the Religious Orders Study who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. p75(NTR) expression within male cholinergic NB neurons was unchanged across clinical diagnosis, whereas p75(NTR) mRNA levels in female NB neurons exhibited a approximately 40% reduction in AD compared to NCI. Male AD subjects displayed a approximately 45% reduction in trkA mRNA levels within NB neurons compared to NCI and MCI. In contrast, NB neuronal trkA expression in females was reduced approximately 50% in both MCI and AD compared to NCI. Reduced trkA mRNA levels were associated with poorer global cognitive performance and higher Braak scores in the female subjects. In addition, we found a female-selective reduction in GluR2 AMPA glutamate receptor subunit expression in NB neurons in AD. These data suggest that cholinergic NB neurons in females may be at greater risk for degeneration during the progression of AD and support the concept of gender-specific therapeutic interventions during the preclinical stages of the disease.