The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma.

This phase 2 study evaluated the activity and safety of ibrutinib, a Bruton's tyrosine kinase inhibitor, plus rituximab in adults with previously untreated follicular lymphoma. Patients received once-daily ibrutinib 560 mg continuously plus once-weekly rituximab 375 mg/m2 for 4 weeks beginning Week 1 (Arm 1, n = 60) or Week 9 (following an 8-week ibrutinib lead-in) to explore biomarkers (Arm 2, n = 20). The primary endpoint was the best overall response rate (ORR). The median age was 58 years; most had an Eastern Cooperative Oncology Group Performance Status of 0 (74%) and Stage III/IV disease (84%). At a median study follow-up of 34 months in Arm 1 and 29 months in Arm 2, ORRs were 85% [95% confidence interval (CI) 73-93] and 75% (95% CI 51-91), respectively, with complete responses in 40% and 50%. The median duration of response was not reached in either arm; 30-month progression-free and overall survival rates were 67% and 97% (Arm 1) and 65% and 100% (Arm 2). The most common adverse events were fatigue, diarrhoea and nausea. Higher grade (Grade 3/4) haematological, haemorrhagic and cardiac events occurred infrequently. Ibrutinib plus rituximab was active and tolerable in first-line follicular lymphoma.

The novel mitochondrial iron chelator 5-((methylamino)methyl)-8-hydroxyquinoline protects against mitochondrial-induced oxidative damage and neuronal death.

Abundant evidence indicates that iron accumulation, oxidative damage and mitochondrial dysfunction are common features of Huntington's disease, Parkinson's disease, Friedreich's ataxia and a group of disorders known as Neurodegeneration with Brain Iron Accumulation. In this study, we evaluated the effectiveness of two novel 8-OH-quinoline-based iron chelators, Q1 and Q4, to decrease mitochondrial iron accumulation and oxidative damage in cellular and animal models of PD. We found that at sub-micromolar concentrations, Q1 selectively decreased the mitochondrial iron pool and was extremely effective in protecting against rotenone-induced oxidative damage and death. Q4, in turn, preferentially chelated the cytoplasmic iron pool and presented a decreased capacity to protect against rotenone-induced oxidative damage and death. Oral administration of Q1 to mice protected substantia nigra pars compacta neurons against oxidative damage and MPTP-induced death. Taken together, our results support the concept that oral administration of Q1 is a promising therapeutic strategy for the treatment of NBIA.

Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia.

Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms.

Crystallization of Lactose-Protein Solutions in the Presence of Flavonoids.

Lactose is commonly crystallized in the presence of whey proteins, forming co-crystals of lactose and proteins. This work hypothesized that flavonoids such as rutin or epigallocatechin-3-gallate (EGCG) could be incorporated into the lactose and protein co-crystal structure since flavonoids may interact with both lactose and proteins. The interactions between whey proteins and flavonoids were first studied. Then, lactose-protein solutions were crystallized with and without flavonoids, measuring the kinetic parameters of crystallization and characterizing the resulting crystals. The incorporation of flavonoids in lactose-protein co-crystals depended on the hydrophilic nature of flavonoids. The hydrophilic EGCG was scarcely enclosed in the crystal lattice of lactose and avoided the inclusion of whey proteins in the crystals. In contrast, the less water-soluble rutin interacted with whey proteins and lactose, leading to the formation of co-crystals containing lactose, protein, and a large concentration of rutin (3.468 ± 0.392 mg per 100 mg of crystals).

The chronic administration of cerebrolysin induces plastic changes in the prefrontal cortex and dentate gyrus in aged mice.

Cerebrolysin (Cbl) is a mixture of neuropeptides with effects similar to the endogenous neurotrophic factors and is considered one of the best drugs used in the treatment of dementias such as Alzheimer's disease (AD). In brains with AD, morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of this drug on the dendrites of pyramidal neurons of the PFC and CA1 dorsal hippocampus and granule cells from the dentate gyrus (DG) and medium spiny neurons of the nucleus accumbens (NAcc) of aged mice. Cbl (5 ml kg(-1) , i.p.) was administered daily for 60 days to 6-month-old mice. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 8 months ages. In all Cbl-treated mice a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC and granule cells of the DG was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC whereas in granule neurons of the DG the increase in dendritic length was further from the soma. Our results suggest that Cbl induces plastic modifications of dendritic morphology in the PFC and DG. These changes may explain the therapeutic effect seen in AD patients treated with Cbl.

Enhanced dendritic spine number of neurons of the prefrontal cortex, hippocampus, and nucleus accumbens in old rats after chronic donepezil administration.

In Alzheimer's disease brains, morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been observed. These changes are particularly reflected in the decrement of both the dendritic tree and spine number. Donepezil is a potent and selective acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease. We have studied the effect of oral administration of this drug on the morphology of neuronal cells from the brain of aged rats. We examined dendrites of pyramidal neurons of the PFC, dorsal or ventral hippocampus (VH), and medium spiny neurons of the nucleus accumbens (NAcc). Donepezil (1 mg/kg, vo) was administrated every day for 60 days to rats aged 10 and 18 months. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 12 and 20 months ages, respectively. In all Donepezil-treated rats, a significant increment of the dendritic spines number in pyramidal neurons of the PFC and dorsal hippocampus was observed. However, pyramidal neurons of the VH and medium spiny cells of the NAcc only showed an increase in the number of their spines in 12-month-old rats. Our results suggest that Donepezil prevents the alterations of the neuronal dendrite morphology caused by aging.

Individual and combined effect of pH and whey proteins on lactose crystallization.

Lactose is recovered by crystallization from cheese whey that is a by-product of cheesemaking. The whey used for the recovery of lactose usually has a residual content of protein that alters the crystallization of lactose. In addition, the pH of whey may fluctuate depending on the cheese variety. However, there is little information on how the pH modifies the effect that whey proteins have on lactose crystallization. Accordingly, this work aimed to evaluate the individual and combined effect of whey proteins and pH on the kinetics of crystallization, the crystal size distribution and the crystallinity of lactose. The addition of whey proteins in lactose solutions (25% v/v) modified the process of lactose crystallization. However, the effect that whey proteins had on lactose crystallization heavily depended on the pH. The number of crystals per milliliter as well as the growth and size distribution of crystals was the most affected with the changes in pH (pHs of 7, 5.5 and 4) and the addition of whey proteins (0 and 0.63%). All the treatment produced mostly α-lactose monohydrated but some treatments also generated crystals of ß-lactose (pH 5.5, 0% of proteins). Amorphous lactose was observed mainly in lactose solutions adjusted at pH 7 and added with whey proteins. This particular treatment also incorporated the highest amount of protein into the lattice of lactose crystals. The results of this work highlight the importance of controlling the pH of lactose crystallization, especially if there is a presence of whey proteins.

Accumulation of aspartic acid421- and glutamic acid391-cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease.

Truncations of tau protein at aspartic acid421 (D421) and glutamic acid391 (E391) residues are associated with neurofibrillary tangles (NFTs) in the brains of Alzheimer disease (AD) patients. Using immunohistochemistry with antibodies to D421- and E391-truncated tau (Tau-C3 and MN423, respectively), we correlated the presence of NFTs composed of these truncated tau proteins with clinical and neuropathologic parameters in 17 AD and 23 non-AD control brains. The densities of NFTs composed of D421- or E391-truncated tau correlated with clinical dementia index and Braak staging in AD. Glutamic acid391 tau truncation was prominent in the entorhinal cortex, whereas D421 truncation was prominent in the subiculum, suggesting that NFTs composed of either D421- or E391-truncated tau may be formed mutually exclusively in these areas. Both truncations were associated with the prevalence of the apolipoprotein E epsilon4 allele. By double labeling, intact tau in NFTs was commonly associated with D421-cleaved tau but not with E391-truncated tau; D421-cleaved tau was never associated with E391-truncated tau. These results indicate that tau is not randomly proteolyzed at different domains, and that proteolysis occurs sequentially from the C-terminus to inner regions of tau in AD progression. Identification of NFTs composed of tau at different stages of truncation may facilitate assessment of neurofibrillary pathology in AD.

Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer's disease.

Phosphorylation, cleavage and conformational changes in tau protein all play pivotal roles during Alzheimer's disease (AD). In an effort to determine the chronological sequence of these changes, in this study, using confocal microscopy, we compared phosphorylation at several sites (Ser(199/202/396/404/422)-Thr(205) and the second repeat domain), cleavage of tau (D(421)) and the canonical conformational Alz-50 epitope. While all of these posttranslational modifications are found in neurofibrillary tangles (NFTs) at all stages of the disease, we found significantly higher numbers of phospho-tau positive NFTs when compared with cleaved tau (P = 0.006 in Braak III; P = 0.002 in Braak IV; P = 0.012 in Braak V) or compared with the Alz-50 epitope (P < 0.05). Consistent with these findings, in a double transgenic mice model (Tet/GSK-3beta/VLW) overexpressing the enzyme glycogen synthase kinase-3beta (GSK-3beta) and tau with a triple FTDP-17 mutation (VLW) with AD-like neurodegeneration, phosphorylation at sites Ser(199/202)-Thr(205) was greater than truncated tau. Taken together, these data strongly support the notion that the conformational changes and truncation of tau occur after the phosphorylation of tau. We propose two probable pathways for the pathological processing of tau protein during AD, either phosphorylation and cleavage of tau followed by the Alz-50 conformational change or phosphorylation followed by the conformational change and cleavage as the last step.

Thiazin red as a neuropathological tool for the rapid diagnosis of Alzheimer's disease in tissue imprints.

In recent years, we have used a variety of tau immunological markers combined with the dye thiazin red (TR), an accurate marker to differentiate the fibrillar from the nonfibrillar state of both amyloid-beta and tau in Alzheimer's disease (AD). In this study, we used TR as a potential diagnostic marker of AD in frozen-thawed (F-T) brain tissue and imprint cytology. Control experiments included the use of Thioflavin-S staining, fixed tissue, and some double-labeled material with TR and selected tau markers, including AT100, MC1, Alz-50, TG-3, Tau-C3, and S396. Our results indicate that TR retains its strong affinity for both tangles and plaques in unfixed F-T tissue and imprint cytology. This information provides a potential use of TR as an accurate diagnostic tool for the rapid postmortem diagnosis of AD neuropathology. This study shows the advantages of TR on cytology mainly because tools for the fast postmortem diagnosis of AD are practically nonexistent. In addition, we observed Tau-C3 immunoreactivity in extracellular tangles, suggesting that the Tau-C3 epitope is characteristically stable. Moreover, this study demonstrates that chemical fixation is not necessarily required for tau immunoreactivity on histological sections.

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma.

PURPOSE: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. PATIENTS AND METHODS: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. RESULTS: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease.

Neurofibrillary tangles (NFT) and dystrophic neurites represent dense cytoplasmic accumulations of abnormal polymers in the brain of patients with Alzheimer's disease (AD). These polymers are referred to as paired helical filaments (PHFs) whose main structural core is composed of tau protein. Tau processing has been associated with hyperphosphorylation and truncation that results in PHF assembly. Both molecular events appear to cause conformational change of tau molecules [11,17,32]. In this regard, in a previous work focused on the analysis of patterns of immunolabeling in pre-tangle cells, we found that regional changes precede the structural modifications in tau [32]. In the present study, we further analyzed the early stages of tau processing in pre-tangle cells by using a variety of immunological markers of specific N-terminus phosphorylation tau sites. We used AT100, TG-3, AT8, pT231, Alz-50, Tau-C3 and 423 antibodies that recognize different abnormal tau epitopes in AD brains. These antibodies were combined and analyzed using a confocal microscope. Our results indicate that the early stages of abnormal tau processing are characterized by a sequential appearance of specific phospho-dependent epitope. The cascade of appearance of the antibodies is: pT231 --> TG-3 --> AT8 -->AT100 --> Alz-50. In addition; truncation at Asp-421 of the C-terminus of tau protein, as detected by Tau-C3, is also an early molecular event in tau protein aggregation prior to PHF formation in AD.

Community-based trial of R-CHOP and maintenance rituximab for intermediate- or high-grade non-Hodgkin lymphoma with first-cycle filgrastim for older patients.

BACKGROUND: Administration of full-dose R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy is important to maximize response in patients with intermediate-or high-grade non-Hodgkin lymphoma but might be difficult in older patients. PATIENTS AND METHODS: This community-based study was conducted to determine response, toxicity, and disease-free survival in patients with intermediate-or high-grade non-Hodgkin lymphoma receiving R-CHOP with filgrastim. Patients received 6-8 cycles of R-CHOP followed by 4 cycles of maintenance rituximab for responders. Patients aged > 60 years or with increased infection risk received filgrastim 5 microg/kg per day in all R-CHOP cycles; other patients received filgrastim after a neutropenic event (no planned administration for cycle 1). RESULTS: Of 101 patients enrolled, 60 (59%) were aged > 60 years and received filgrastim in all cycles. Thirty-three patients aged 60 years vs. 93% 60 years vs. 95% 60 years vs. 71% 60 years vs. 78% or= 38.3 degrees C with absolute neutrophil count < 500/mm) occurred in 17% of patients overall (22% > 60 years vs. 10% 60 years vs. 2% 60 years receiving R-CHOP with filgrastim support in all cycles received comparable doses of chemotherapy and had similar overall response rates compared wtih those of younger patients receiving no preemptive cycle-1 filgrastim.

Data set of interactomes and metabolic pathways of proteins differentially expressed in brains with Alzheimer׳s disease.

Alzheimer׳s disease is one of the main causes of dementia in the elderly and its frequency is on the rise worldwide. It is considered the result of complex interactions between genetic and environmental factors, being many of them unknown. Therefore, there is a dire necessity for the identification of novel molecular players for the understanding of this disease. In this data article we determined the protein expression profiles of whole protein extracts from cortex regions of brains from patients with Alzheimer׳s disease in comparison to a normal brain. We identified 721 iTRAQ-labeled polypeptides with more than 95% in confidence. We analyzed all proteins that changed in their expression level and located them in the KEGG metabolic pathways, as well as in the mitochondrial complexes of the electron transport chain and ATP synthase. In addition, we analyzed the over- and sub-expressed polypeptides through IPA software, specifically Core I and Biomarkers I modules. Data in this article is related to the research article "Identification of proteins that are differentially expressed in brains with Alzheimer's disease using iTRAQ labeling and tandem mass spectrometry" (Minjarez et al., 2016) [1].

Identification of proteins that are differentially expressed in brains with Alzheimer's disease using iTRAQ labeling and tandem mass spectrometry.

Alzheimer's disease is one of the leading causes of dementia in the elderly. It is considered the result of complex events involving both genetic and environmental factors. To gain further insights into this complexity, we quantitatively analyzed the proteome of cortex region of brains from patients diagnosed with Alzheimer's disease, using a bottom-up proteomics approach. We identified 721 isobaric-tagged polypeptides. From this universe, 61 were found overexpressed and 69 subexpressed in three brains with Alzheimer's disease in comparison to a normal brain. We determined that the most affected processes involving the overexpressed polypeptides corresponded to ROS and stress responses. For the subexpressed polypeptides, the main processes affected were oxidative phosphorylation, organellar acidification and cytoskeleton. We used Drosophila to validate some of the hits, particularly those non-previously described as connected with the disease, such as Sideroflexin and Phosphoglucomutase-1. We manipulated their homolog genes in Drosophila models of Aß- and Tau-induced pathology. We found proteins that can either modify Aß toxicity, Tau toxicity or both, suggesting specific interactions with different pathways. This approach illustrates the potential of Drosophila to validate hits after MS studies and suggest that model organisms should be included in the pipeline to identify relevant targets for Alzheimer's disease. BIOLOGICAL SIGNIFICANCE: We report a set of differentially expressed proteins in three Alzheimer's disease brains in comparison to a normal brain. Our analyses allowed us to identify that the main affected pathways were ROS and stress responses, oxidative phosphorylation, organellar acidification and cytoskeleton. We validated some identified proteins using genetic models of Amyloid-ß and Tau-induced pathology in Drosophila melanogaster. With this approach, Sideroflexin and Phosphoglucomutase-1 were identified as novel proteins connected with Alzheimer's disease.

Fibrillar Amyloid-ß Accumulation Triggers an Inflammatory Mechanism Leading to Hyperphosphorylation of the Carboxyl-Terminal End of Tau Polypeptide in the Hippocampal Formation of the 3×Tg-AD Transgenic Mouse.

Alzheimer's disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-ß (Aß) asneurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aß and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenicmouse, we determined the accumulation of fibrillar Aß as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of wholeprotein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aß deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aß oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide.

Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer's disease.

Neurofibrillary tangles (NFTs) are the neuropathological hallmarks in Alzheimer's disease (AD). Densities of NFTs correlate with the dementia status. NFTs reflect the intracellular accumulation of abnormal paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Hyperphosphorylation and truncation have been proposed as key events leading to the genesis of PHFs. A recent hypothesis involving conformational changes has been emerging. These structural modifications of the tau protein were detected by monoclonal antibodies (mAbs) recognizing discontinuous epitopes along the tau molecule such as Alz-50, Tau-66 and MC1. A new mAb, TG-3, detects an early pathology in AD. The epitope of mAb TG-3 maps to phosphorylated Thr231 when the tau molecule is conformationally altered. In the present study, we used confocal microscopy to analyze the state of tau molecule adopting the TG-3 conformation during tangle formation. We also compared mAb TG-3 immunoreactivity with that of mAb Alz-50. Immunoelectronmicroscopy was also performed. N- and C- termini markers evidenced that the tau molecule is intact when it adopts the TG-3 conformation. In addition to NFT, mAb TG-3 also recognized NFT-not bearing-neurons suggesting an early processing of tau prior to NFT formation. Ultrastructural analysis evidenced the presence of TG-3 and Alz-50 immunoreactive products on organelles including mitochondria and endoplasmic reticulum. Nuclear heterochromatin was densely immunolabelled. These results together with the fact that TG-3 immunoreactivity is related to intact tau suggest that the conformation recognized by TG-3 is early staged in the neuronal pathology of AD. In addition, we document that the earliest changes in tau occur closely associated with organelles and heterochromatin.

The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer's disease.

We previously demonstrated that, in the early stages of tau processing in Alzheimer's disease, the N-terminal part of the molecule undergoes a characteristic cascade of phosphorylation and progressive misfolding of the proteins resulting in a structural conformation detected by Alz-50. In this immunohistochemical study of AD brain tissue, we have found that C-terminal truncation of tau at Asp-421 was an early event in tau aggregation and analyzed the relationship between phospho-dependent tau epitopes located at the C-terminus with truncation at Glu-391. The aim of this study was to determine whether C-terminal truncation may trigger events leading to the assembly of insoluble PHFs from soluble tau aggregates present in pre-tangle cells. Our findings suggest that there is a complex interaction between phosphorylated and truncated tau species. A model is presented here in which truncated tau protein represents an early neurotoxic species while phosphorylated tau species may provide a neuroprotective role in Alzheimer's disease.

Mutant Taiep rats exhibit an increase in D1 binding in basal ganglia.

Previous reports have shown that the Taiep rat develop a progressive neurological syndrome characterized by tremor, ataxia, immobility episodes, audiogenic seizures and hind limb paralysis. Here we have investigated whether differences in levels of dopamine D1-like and D2-like receptors could be correlated with the progression of this neurological syndrome. Comparative autoradiographic study of Taiep and Sprague-Dawley (SD) rats at level of basal ganglia and limbic subregion were undertaken in 3- and 9-month-old rats. The Taiep rats exhibited a higher level of D1 receptors in the basal ganglia subregions compared to SD. However, there were no differences in the level of D1 receptors in the limbic subregions between these two strains. As compared to the SD rats, the Taiep rats did not appear to change levels of D2-like receptors. These data suggest that the differences in D1 receptors in these two strains rats may in part contribute to develop the dopamine related symptoms seen in the mutant rat, such as tremor, which is the earliest sign of the Taiep rat syndrome.