Biomedical subjects

Daniel M Skovronsky

Publications and source records attributed to Daniel M Skovronsky.

5 recordsLinked to original sources

PubMed2004

Pathologic classification of peripheral nerve tumors.

Peripheral nerve tumors show an interesting histologic variety despite being composed ofa limited array of cellular constituents. As we learn more about the interplay between the Schwann cells, perineurial cells, and ganglion cells that comprise these tumors, it is likely that we will better understand the biologic behavior of these important tumors. Key issues for the pathologist include distinguishing schwannomas from neurofibromas, ganglioneuromas from neurofibromas involving ganglia, and MPNSTs from cellular schwannomas or neurofibromas. The association of each of these tumors with genetic tumor disorders provides a unique window into discovering basic mechanisms of cell regulation and tumorigenesis that may ultimately shed light on the biology of a much wider array of human disease.

Ganglioneuroma↗

PubMed2003

Detection of amyloid plaques by radioligands for Abeta40 and Abeta42: potential imaging agents in Alzheimer's patients.

Alzheimer s disease (AD) is linked to increased brain deposition of amyloid-beta (Abeta) peptides in senile plaques (SPs), and recent therapeutic efforts have focused on inhibiting the production or enhancing the clearance of Abeta in brain. However, it has not been possible to measure the burden of SPs or assess the effect of potential therapies on brain Abeta levels in patients. Toward that end, we have developed a novel radioligand, [(125)I]TZDM, which binds Abeta fibrils with high affinity, crosses the blood-brain barrier (BBB), and labels amyloid plaques in vivo. Compared to a styrylbenzene probe, [(125)I]IMSB, [(125)I]TZDM showed a 10-fold greater brain penetration and labeled plaques with higher sensitivity for in vivo imaging. However, this ligand also labels white matter, which contributes to undesirable high background regions of the brain. Interestingly, parallel to their differential binding characteristics onto fibrils composed of 40 (Abeta40)- or 42 (Abeta42)-amino-acid-long forms of Abeta peptides, these radioligands displayed differential labeling of SPs in AD brain sections under our experimental conditions. It was observed that [(125)I]IMSB labeled SPs containing Abeta40, amyloid angiopathy (AA), and neurofibrillary tangles, whereas [(125)I]TZDM detected only SPs and Abeta42-positive AA. Since increased production and deposition of Abeta42 relative to Abeta40 may be crucial for the generation of SPs, [(125)I]TZDM and related derivatives may be more attractive probes for in vivo plaque labeling. Further structural modifications of TZDM to lower the background labeling will be needed to optimize the plaque-labeling property.

Alzheimer Disease↗

PubMed2002

Secretion and intracellular generation of truncated Abeta in beta-site amyloid-beta precursor protein-cleaving enzyme expressing human neurons.

Insoluble pools of the amyloid-beta peptide (Abeta) in brains of Alzheimer's disease patients exhibit considerable N- and C-terminal heterogeneity. Mounting evidence suggests that both C-terminal extensions and N-terminal truncations help precipitate amyloid plaque formation. Although mechanisms underlying the increased generation of C-terminally extended peptides have been extensively studied, relatively little is known about the cellular mechanisms underlying production of N-terminally truncated Abeta. Thus, we used human NT2N neurons to investigate the production of Abeta11-40/42 from amyloid-beta precursor protein (APP) by beta-site APP-cleaving enzyme (BACE). When comparing undifferentiated human embryonal carcinoma NT2- cells and differentiated NT2N neurons, the secretion of sAPP and Abeta correlated with BACE expression. To study the effects of BACE expression on endogenous APP metabolism in human cells, we overexpressed BACE in undifferentiated NT2- cells and NT2N neurons. Whereas NT2N neurons produced both full-length and truncated Abeta as a result of normal processing of endogenous APP, BACE overexpression increased the secretion of Abeta1-40/42 and Abeta11-40/42 in both NT2- cells and NT2N neurons. Furthermore, BACE overexpression resulted in increased intracellular Abeta1-40/42 and Abeta11-40/42. Therefore, we conclude that Abeta11-40/42 is generated prior to deposition in senile plaques and that N-terminally truncated Abeta peptides may contribute to the downstream effects of amyloid accumulation in Alzheimer's disease.

Alzheimer Disease↗

PubMedDate not supplied

Radioiodinated styrylbenzene derivatives as potential SPECT imaging agents for amyloid plaque detection in Alzheimer's disease.

Development of probes for beta-amyloid (A beta) plaques, a critical factor associated with Alzheimer's disease (AD), provides important tools for studying their role in AD. Previously, we reported [125I]IMSB and [125I]ISB as excellent probes for A beta plaque labeling. Despite their exquisite in vitro binding characteristics, low brain uptakes (likely due to two ionizable carboxylic acid groups) limited their potential as in vivo imaging agents. To improve brain penetration, we have successfully prepared a neutral radioiodinated probe [125I]3. The improved probe displayed good binding affinity for A beta aggregates (Ki = 2.0 +/- 0.2 using A beta40 aggregates). In addition, the brominated counterpart displayed fluorescent-staining properties of A beta plaques in postmortem AD brain sections similar to BSB, a fluoroscent probe reported previously. [125I]3 gave excellent plaque labeling by film autoradiography of AD brain sections. Unlike [125I]IMSB (which preferentially detects A beta40 plaques), the improved radioioinated probe, [125I]3, can readily detect plaques containing aggregates of both A beta40 and A beta42. The initial brain uptake of [125I]3 in normal mice at 2 min p.i. was moderate (0.18% ID) and displayed a very slow washout from the brain (0.11%.ID at 4 h p.i). Taken together, these data suggest that [125I]3 is useful for in vitro plaque detection, it may not be suitable for in vivo monitoring of A beta progression and deposition.

Alzheimer Disease↗

PubMedDate not supplied

Iodinated tracers for imaging amyloid plaques in the brain.

Excessive amounts of protein deposits, beta-amyloid (Abeta) plaques, are commonly detected in the postmortem brains of Alzheimer's disease (AD) patients. These Abeta plaques are believed to play an important role in the pathogenesis of the disease. Development of Abeta plaque-specific imaging agents for detecting and monitoring the changes of Abeta plaque deposition in living brains are reported. These agents, if successfully developed, may serve as potential biomarkers for the disease. Several iodinated derivatives based on variety of core structures are labeled with radioiodine as single photon emission computed tomography (SPECT) imaging agents. Thioflavin (or benzothiazole) derivatives displayed excellent in vitro characteristics with high binding affinities for Abeta aggregates (in subnanomolar to nanomolar range) and excellent plaque labeling of AD brain sections. However, the in vivo kinetic properties appeared unfavorable for further development. A novel series of imidazo-pyridine derivative, such as 2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine (IMPY), exhibited highly desirable in vivo properties. Additional structural modification resulting in stilbene derivatives displayed good binding affinities for Abeta aggregates. In addition, fluorene compounds with a rigid tricyclic structure showed in vitro and in vivo characteristics as potential SPECT imaging agents. Criteria for selection of radioiodinated tracers with suitable in vivo properties to detect amyloid plaques are discussed.

Alzheimer Disease↗