Biomedical subjects

Robert P Brendza

Publications and source records attributed to Robert P Brendza.

6 recordsLinked to original sources

PubMed2005

Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice.

Neuritic plaques are a defining feature of Alzheimer disease (AD) pathology. These structures are composed of extracellular accumulations of amyloid-beta peptide (Abeta) and other plaque-associated proteins, surrounded by large, swollen axons and dendrites (dystrophic neurites) and activated glia. Dystrophic neurites are thought to disrupt neuronal function, but whether this damage is static, dynamic, or reversible is unknown. To address this, we monitored neuritic plaques in the brains of living PDAPP;Thy-1:YFP transgenic mice, a model that develops AD-like pathology and also stably expresses yellow fluorescent protein (YFP) in a subset of neurons in the brain. Using multiphoton microscopy, we observed and monitored amyloid through cranial windows in PDAPP;Thy-1:YFP double-transgenic mice using the in vivo amyloid-imaging fluorophore methoxy-X04, and individual YFP-labeled dystrophic neurites by their inherent fluorescence. In vivo studies using this system suggest that amyloid-associated dystrophic neurites are relatively stable structures in PDAPP;Thy-1:YFP transgenic mice over several days. However, a significant reduction in the number and size of dystrophic neurites was seen 3 days after Abeta deposits were cleared by anti-Abeta antibody treatment. This analysis suggests that ongoing axonal and dendritic damage is secondary to Abeta and is, in part, rapidly reversible.

Alzheimer Disease↗

PubMed2004

Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition.

Increasing evidence demonstrates that there is marked damage and dysfunction not only in the gray matter but also in the white matter in Alzheimer's disease (AD). In this study, transgenic mice overexpressing beta-amyloid precursor protein (APP) under control of the platelet-derived growth factor promoter (PDAPP mice) were examined using diffusion tensor magnetic resonance imaging (DTI) to evaluate the extent of white matter injury before and following the development of AD-like pathology. The profile of DTI parameters was significantly different in old PDAPP mice compared to that of old control mice following the development of AD-like pathology. No difference in DTI parameters was observed between the young PDAPP and control mice. Our results suggest that as amyloid beta (Abeta) deposition and levels increase over time in PDAPP mice, these changes lead to primary or secondary white matter injury that can be detected by DTI.

Aging↗

PubMed2003

PDAPP; YFP double transgenic mice: a tool to study amyloid-beta associated changes in axonal, dendritic, and synaptic structures.

Neuritic plaques are one of the stereotypical hallmarks of Alzheimer's disease (AD) pathology. These structures are composed of extracellular accumulations of fibrillar forms of the amyloid-beta peptide (Abeta), a variety of other plaque-associated proteins, activated glial cells, and degenerating nerve processes. To study the neuritic toxicity of different structural forms of Abeta in the context of regional connectivity and the entire cell, we crossed PDAPP transgenic (Tg) mice, a model with AD-like pathology, to Tg mice that stably express yellow fluorescent protein (YFP) in a subset of neurons in the brain. In PDAPP; YFP double Tg mice, markedly enlarged YFP-labeled axonal and dendritic varicosities were associated with fibrillar Abeta deposits. These varicosities were absent in areas where there were nonfibrillar Abeta deposits. Interestingly, YFP-labeled varicosities revealed changes that corresponded with changes seen with electron microscopy and the de Olmos silver staining technique. Other silver staining methods and immunohistochemical localization of phosphorylated neurofilaments or phosphorylated tau were unable to detect the majority of these dystrophic neurites. Some but not all synaptic vesicle markers accumulated abnormally in YFP-labeled varicosities associated with neuritic plaques. In addition to the characterization of the effects of Abeta on axonal and dendritic structure, YFP-labeled neurons in Tg mice should prove to be a valuable tool to interpret the localization patterns of other markers and for future studies examining the dynamics of axons and dendrites in a variety of disease conditions in living tissue both in vitro and in vivo.

Alzheimer Disease↗

PubMed2003

Use of YFP to study amyloid-beta associated neurite alterations in live brain slices.

Neuritic plaques are one of the defining neuropathological features of Alzheimer's disease (AD). These structures are composed of a buildup of fibrils of the amyloid-beta (Abeta) peptide (amyloid) surrounded by activated glial cells and degenerating nerve processes (dystrophic neurites). To study neuritic plaques and possible abnormalities associated with dendrites, axons, and synaptic structures, we have developed an acute slice preparation model using PDAPP, yellow fluorescent protein (YFP) double transgenic mice (a mouse model with AD-like pathology that stably expresses YFP in a subset of neurons in the brain). With laser scanning confocal microscopy, we have imaged living brain slices from PDAPP, YFP double transgenic mice as old as 20 months and have been able to visualize axons, dendrites, dendritic spines, and dystrophic neurites for many hours. Our initial studies suggest that dystrophic axons and dendrites within neuritic plaques are fairly stable structures in the absence of exogenous perturbations. This acute slice preparation model should prove to be a useful tool to explore the pathophysiology of Abeta-related axonal, dendritic, and synaptic dysfunction.

Alzheimer Disease↗

PubMed2002

Posterior localization of dynein and dorsal-ventral axis formation depend on kinesin in Drosophila oocytes.

To establish the major body axes, late Drosophila oocytes localize determinants to discrete cortical positions: bicoid mRNA to the anterior cortex, oskar mRNA to the posterior cortex, and gurken mRNA to the margin of the anterior cortex adjacent to the oocyte nucleus (the "anterodorsal corner"). These localizations depend on microtubules that are thought to be organized such that plus end-directed motors can move cargoes, like oskar, away from the anterior/lateral surfaces and hence toward the posterior pole. Likewise, minus end-directed motors may move cargoes toward anterior destinations. Contradicting this, cytoplasmic dynein, a minus-end motor, accumulates at the posterior. Here, we report that disruption of the plus-end motor kinesin I causes a shift of dynein from posterior to anterior. This provides an explanation for the dynein paradox, suggesting that dynein is moved as a cargo toward the posterior pole by kinesin-generated forces. However, other results present a new transport polarity puzzle. Disruption of kinesin I causes partial defects in anterior positioning of the nucleus and severe defects in anterodorsal localization of gurken mRNA. Kinesin may generate anterodorsal forces directly, despite the apparent preponderance of minus ends at the anterior cortex. Alternatively, kinesin I may facilitate cytoplasmic dynein-based anterodorsal forces by repositioning dynein toward microtubule plus ends.

Animals↗

PubMedDate not supplied

Amyloid-beta immunotherapies in mice and men.

Given the compelling genetic and biochemical evidence that has implicated amyloid-beta (Abeta) in the pathogenesis of Alzheimer's disease, many studies have focused on ways to inhibit Abeta production, to reverse or impede the formation of toxic forms of Abeta, or to facilitate the clearance of Abeta from the brain, in the hope of developing viable treatments for the disease. Using transgenic mouse models of Alzheimer's disease, many advances have been made in methodologies using different immunization techniques designed to clear soluble and aggregated forms of Abeta from the brain. We have highlighted how data derived from studies using transgenic mouse models have shaped our understanding of immunization-dependent Abeta clearance mechanisms and how these studies have influenced the development of anti-Abeta immunotherapies in humans.

Alzheimer Disease↗