Faculty Bibliography

In this study, we used MRI to analyze quantitative parametric maps of transverse (T(2)) relaxation times in a longitudinal study of transgenic mice expressing mutant forms of amyloid precursor protein (APP), presenilin (PS1), or both (PS/APP), modeling aspects of Alzheimer's disease (AD). The main goal was to characterize the effects of progressive beta-amyloid accumulation and deposition on the biophysical environment of water and to investigate if these measurements would provide early indirect evidence of AD pathological changes in the brains of these mice. Our results demonstrate that at an early age before beta-amyloid deposition, only PS/APP mice show a reduced T(2) in the hippocampus and cortex compared with wild-type non-transgenic (NTg) controls, whereas a statistically significant within-group aging-associated decrease in T(2) values is seen in the cortex and hippocampus of all three transgenic genotypes (APP, PS/APP, and PS) but not in the NTg controls. In addition, for animals older than 12 months, we confirmed our previous report that only the two genotypes that form amyloid plaques (APP and PS/APP) have significantly reduced T(2) values compared with NTg controls. Thus, T(2) changes in these AD models can precede amyloid deposition or even occur in AD models that do not deposit beta-amyloid (PS mice), but are intensified in the presence of amyloid deposition

The main objective of this study was to investigate the biological function of beta amyloid precursor protein (APP), in particular its nerve growth factor-like activity. We hypothesize that the extracellular domain containing the sequence RERMS, amino acids 328-332 of APP(695), represents the active site for this function. Binding assays using peptide fragments of this domain have demonstrated specific and saturable binding to the cell surface with affinity in the low nanomolar range. This induced our quest for an APP-specific receptor. We chose different peptide fragments of the RERMS domain as ligands and displacing agents on affinity columns to purify APP-binding molecules. Amino acid microsequencing yielded partial sequences of serum albumin, actin, two novel proteins of 41 and 63kDa, and human Collapsin Response Mediator Protein-2 (hCRMP-2). Because both APP and hCRMP-2 promote neuronal outgrowth and use a common signaling pathway, APP could be acting through a semaphorin receptor as well

We have shown that neuropeptide Y (NPY) regulates neurogenesis in the normal dentate gyrus (DG) via Y(1) receptors (Howell, O.W., Scharfman, H.E., Herzog, H., Sundstrom, L.E., Beck-Sickinger, A. and Gray, W.P. (2003) Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells. J Neurochem, 86, 646-659; Howell, O.W., Doyle, K., Goodman, J.H., Scharfman, H.E., Herzog, H., Pringle, A., Beck-Sickinger, A.G. and Gray, W.P. (2005) Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus. J Neurochem, 93, 560-570). This regulation may be relevant to epilepsy, because seizures increase both NPY expression and precursor cell proliferation in the DG. Therefore, the effects of NPY on DG precursors were evaluated in normal conditions and after status epilepticus. In addition, potentially distinct NPY-responsive precursors were identified, and an analysis performed not only of the DG, but also the caudal subventricular zone (cSVZ) and subcallosal zone (SCZ) where seizures modulate glial precursors. We show a proliferative effect of NPY on multipotent nestin cells expressing the stem cell marker Lewis-X from both the DG and the cSVZ/SCZ in vitro. We confirm an effect on proliferation in the cSVZ/SCZ of Y(1) receptor(-/-) mice and demonstrate a significant reduction in basal and seizure-induced proliferation in the DG of NPY(-/-) mice

Evidence suggests that beta-amyloid (Abeta) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer's disease (AD). However, the causal link between Abeta and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Abeta ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD

OBJECTIVE: To analyze the outcomes and complications after total knee replacement (TKR) with posterior stabilized prosthesis (PS) and to investigate the influencing factors relating to outcomes. METHODS: From January 1998 to August 2004, 60 cases (74 knees) of osteoarthritis underwent TKR with PS. The outcomes were evaluated according to the HSS (hospital for special surgery) scoring. The difference in outcomes between patients with post-operative complications and without complications were compared. Pearson correlation was used to analyze postoperative outcomes and the pre-operative factors relating to patients. RESULTS: All 74 knees were followed up 42.5 months (24 to 94 months). The scores for HSS, pain, function, ROM muscle strength, flexion deformity and stability of knees after operation were 84.2 +/- 14.2, 25.7 +/- 6.9, 17.9 +/- 4.3, 13.1 +/- 2.0, 9.2 +/- 0.8, 8.1 +/- 0.4 and 9.3 +/- 0.1 respectively. They were improved to some extents, especially pain alleviation was remarkable. The excellent and good rate for outcome assessment was 90.5%. Among 74 knees, 10 cases suffered from post-operative complications, including 1 case of common peroneal nerve paralysis, two cases of wound faulty union, one case of wound infection, one case of joint infection, one case of stiff knee, two cases of deep vein thrombosis and 2 cases of patellofemoral joint complications. The excellent and good rate of outcome in patients with complications (60%) was much lower than that in patients without complication (95.3%),and there was significant difference between them (P < 0.05). Analysis for correlation showed that postoperative HSS score was positively correlative with the postoperative HSS score, pain and function score of knees. The correlation value was 0.523, 0.431 and 0.418 respectively (P < 0.01). Whereas, postoperative HSS score was not correlative with ROM, muscle strength, flexion deformity, stability of knee, age, weight and body mass index (P > 0.05). CONCLUSION: TKR with PS is an effective method for severe osteoarthritis. The outcomes after TKR have a positive correlation with the HSS score, pain and function score of knees before surgery. Complications associating with surgery have a negative influence on outcomes

Granule cells of the mammalian dentate gyrus normally form a discrete layer, and virtually all granule cells migrate to this location. Exceptional granule cells that are positioned incorrectly, in 'ectopic' locations, are rare. Although the characteristics of such ectopic granule cells appear similar in many respects to granule cells located in the granule cell layer, their rare occurrence has limited a full evaluation of their structure and function. More information about ectopic granule cells has been obtained by studying those that develop after experimental manipulations that increase their number. For example, after severe seizures, the number of ectopic granule cells located in the hilus increases dramatically. These experimentally-induced ectopic granule cells may not be equivalent to normal ectopic granule cells necessarily, but the vastly increased numbers have allowed much more information to be obtained. Remarkably, the granule cells that are positioned ectopically develop intrinsic properties and an axonal projection that are similar to granule cells that are located normally, i.e., in the granule cell layer. However, dendritic structure and synaptic structure/function appear to differ. These studies have provided new insight into a rare type of granule cell in the dentate gyrus, and the plastic characteristics of dentate granule cells that appear to depend on the location of the cell body