Abstract: Abnormal protein deposits are a common feature of many human diseases including Alzheimer's disease. In Alzheimer's disease, the appearance of tangles, composed of the microtubule associated protein tau, correlates with both cell death and symptom severity. However, are tau filaments simply markers of disease progression, or are they directly responsible for cell death? Due to conflicting findings from cell and animal models, it remains controversial whether tau polymers or smaller pre-fibrillar aggregates or tau monomers are the toxic species. Indeed, if monomeric or oligomeric species are mediators of disease, formation of larger tau filaments may prove beneficial to affected cells.…This review will examine the findings regarding the toxicity of various tau species.
Show more
Abstract: Microtubule-based axonal transport is believed to become globally disrupted in Alzheimer's disease in part due to alterations of tau expression or phosphorylation. We previously showed that axonal transport rates along retinal ganglion axons are unaffected by deletion of normal mouse tau or by overexpression of wild-type human tau. Here, we report that htau mice expressing 3-fold higher levels of human tau in the absence of mouse tau also display normal fast and slow transport kinetics despite the presence of abnormally hyperphosphorylated tau in some neurons. In addition, markers of slow transport (neurofilament light subunit) and fast transport (snap25) exhibit normal…distributions along optic axons of these mice. These studies demonstrate that human tau overexpression, even when associated with a limited degree of tau pathology, does not necessarily impair general axonal transport function in vivo.
Show more
Abstract: In this communication we report the characterization of several transgenic rat lines expressing human AβPP carrying the Swedish and Indiana mutations (coded UKUR28), the human presenilin 1 transgene with the 'Finn' mutation (coded UKUR19) and double transgenic rats expressing both transgenes (coded UKUR25). In these Tg rats, the AβPP and PS1 transgene expression was largely restricted to the hippocampus and neocortex. The PS1 transgenic rats did not produce visible changes in Aβ immunoreactivity. The AβPP transgenic rats (both the single Tg UKUR28, and double Tg UKUR25) generated a phenotype of intra-neuronalβ accumulation without plaque formation and with no increased immunoreactivity…for AβPP amino and carboxyl-terminal epitopes. This phenotype was apparent as early as 6 months of age in the transgenic rat lines carrying the human AβPP transgene. No senile plaques of aggregated Aβ were observed in any of the transgenic lines generated, up to 24 months of age. The hAβPP single homozygous Tg line (UKUR28) showed an increase in ERK2, without changes in glycogen synthase kinase 3 (GSK3) activity. A preliminary protein analysis of the hippocampus of the double transgenic rat (UKUR25) by mass spectrometry showed differences in the protein profile between this transgenic line and controls.
Show more
Keywords: Amyloid-β, transgenic rat, ERK/MAPK, tau phosphorylation
Abstract: Increasing evidence suggests that oxidative injury is involved in the pathogenesis of many age-related neurodegenerative disorders, including Alzheimer's disease (AD). Identifying the protein targets of oxidative stress is critical to determine which proteins may be responsible for the neuronal impairments and subsequent cell death that occurs in AD. In this study, we have applied a high-throughput shotgun proteomic approach to identify the targets of protein carbonylation in both aged and PS1+AβPP transgenic mice. However, because of the inherent difficulties associated with proteomic database searching algorithms, several newly developed bioinformatic tools were implemented to ascertain a probability-based discernment between correct protein…assignments and false identifications to improve the accuracy of protein identification. Assigning a probability to each identified peptide/protein allows one to objectively monitor the expression and relative abundance of particular proteins from diverse samples, including tissue from transgenic mice of mixed genetic backgrounds. This robust bioinformatic approach also permits the comparison of proteomic data generated by different laboratories since it is instrument- and database-independent. Applying these statistical models to our initial studies, we detected a total of 117 oxidatively modified (carbonylated) proteins, 59 of which were specifically associated with PS1+AβPP mice. Pathways and network component analyses suggest that there are three major protein networks that could be potentially altered in PS1+AβPP mice as a result of oxidative modifications. These pathways are 1) iNOS-integrin signaling pathway, 2) CRE/CBP transcription regulation and 3) rab-lyst vesicular trafficking. We believe the results of these studies will help establish an initial AD database of oxidatively modified proteins and provide a foundation for the design of future hypothesis driven research in the areas of aging and neurodegeneration.
Show more