The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation.

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

SIRT1 deficiency increases O-GlcNAcylation of tau, mediating synaptic tauopathy.

Hyperphosphorylation of the microtubule associated protein tau is associated with several neurodegenerative diseases including Alzheimer's Disease (AD), collectively referred to as tauopathies. However, the mechanisms by which tau is linked to synaptic dysfunction and memory impairment remain unclear. To address this question, we constructed a mouse model with brain-specific deficiency of SIRT1 (SIRT1 flox/Cre + ). Here, we show that increase of site-specific phosphorylation of tau is coupled with the strengthened O-GlcNAcylation of tau triggered by reduced O-GlcNAcase (OGA) and increased O-GlcNAc transferase (OGT) protein level in the brain of SIRT1 flox/Cre+ mice. SIRT1 deletion in mice brain changes the synaptosomal distribution of site-specific phospho-tau. Learning and memory deficiency induced by dendritic spine deficits and synaptic dysfunction are revealed via SIRT1 flox/Cre+ mice. Our results provide evidence for SIRT1 as a potential therapeutic target in clinical tauopathies.

The Role of Amyloid-Beta and Tau in the Early Pathogenesis of Alzheimer's Disease.

The abnormal accumulation of amyloid-b (Ab) and neurofibrillary tangles (NFTs) containing phosphorylated tau proteins are the main histopathological feature of Alzheimer's disease (AD). Synaptic damage and loss are earlier events than amyloid plaques and NFTs in AD progress and best correlate with cognitive deficits in AD patients. Soluble oligomeric Aß initiates the progression of AD and tau mediates the subsequent synaptic impairments at an early stage of AD. In this review we discuss how Ab or/and tau causes synaptic dysfunction. Ab oligomers gather at synapses and give rise to synaptic death in a variety of ways such as regulating receptors and receptor tyrosine kinases, unbalancing calcium homeostasis, and activating caspases and calcineurin. A large amount of hyperphosphorylated tau exists in the synapse of the AD brain. Aß-triggered synaptic deficits are dependent on tau. Soluble, hyperphosphorylated tau is much more correlated to cognitive decline in AD patients. Tau-targeted therapies have received more attention because the treatments targeting Aß failed in AD. Here, we also review the therapy strategies used to intervene in the very early stages of AD. Soluble hyperphosphorylated tau forms a complex with cell surface receptors, scaffold proteins, or intracellular signaling molecules to damage synaptic function. Therefore, therapeutic strategies targeting synaptic tau at the early stage of AD may ameliorating pathology in AD. This review aims to provide an update on the role of oligomeric Ab and soluble hyperphosphorylated tau in the early pathogenesis of Alzheimer's disease and to develop a new treatment strategy based on this.

Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3ß pathway in cells and in APP/PS1 transgenic mice.

Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aß) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3ß pathway. We found GSK3ß increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3ß signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment.

Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I: A MOLECULAR MECHANISM LINKED TO TAU PATHOLOGY IN ALZHEIMER DISEASE.

Hyperphosphorylation and dysregulation of exon 10 splicing of Tau are pivotally involved in pathogenesis of Alzheimer disease (AD) and/or other tauopathies. Alternative splicing of Tau exon 10, which encodes the second microtubule-binding repeat, generates Tau isoforms containing three and four microtubule-binding repeats, termed 3R-Taus and 4R-Taus, respectively. Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) lies at the Down syndrome critical region of chromosome 21. Overexpression of this kinase may contribute to the early Tau pathology in Down syndrome via phosphorylation of Tau and dysregulation of Tau exon 10. Here, we report that Dyrk1A was truncated at the C terminus and was associated with overactivation of calpain I in AD brain. Calpain I proteolyzed Dyrk1A in vitro first at the C terminus and further at the N terminus and enhanced its kinase activity toward Tau via increased Vmax but not Km. C-terminal truncation of Dyrk1A resulted in stronger activity than its full-length protein in promotion of exon 10 exclusion and phosphorylation of Tau. Dyrk1A was truncated in kainic acid-induced excitotoxic mouse brains and coincided with an increase in 3R-Tau expression and phosphorylation of Tau via calpain activation. Moreover, truncation of Dyrk1A was correlated with an increase in the ratio of 3R-Tau/4R-Tau and Tau hyperphosphorylation in AD brain. Collectively, these findings suggest that truncation/activation of Dyrk1A by Ca(2+)/calpain I might contribute to Tau pathology via promotion of exon 10 exclusion and hyperphosphorylation of Tau in AD brain.

Overexpression of Dyrk1A regulates cardiac troponin T splicing in cells and mice.

The human heart expresses four isoforms of cardiac troponin T (cTnT) through alternative splicing of exons 4 and 5 of the cTnT gene. Alternative splicing of cTnT exon 5 is developmentally regulated. cTnT isoforms containing exon 5 are expressed in the fetal and neonatal heart but not in the mature heart. SRp55 is an essential splicing factor involved in cTnT exon 5 splicing and it is phosphorylated by Dyrk1A (dual specificity tyrosine phosphorylation regulated kinase 1A). In the present study, we found Dyrk1A interacted with SRp55 and enhanced its promotion of cTnT exon 5 inclusion. The shift from cTnT exon 5 inclusion to exclusion during development was delayed in the heart of Ts65Dn mice due to Dyrk1A overexpression. These results provide new insight into the role of Dyrk1A in the neonatal cardiac development.

Protein misfolding cyclic amplification induces the conversion of recombinant prion protein to PrP oligomers causing neuronal apoptosis.

The formation of neurotoxic prion protein (PrP) oligomers is thought to be a key step in the development of prion diseases. Recently, it was determined that the sonication and shaking of recombinant PrP can convert PrP monomers into ß-state oligomers. Herein, we demonstrate that ß-state oligomeric PrP can be generated through protein misfolding cyclic amplification from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP, and that these oligomers can be used for subsequent research into the mechanisms of PrP-induced neurotoxicity. We have characterized protein misfolding cyclic amplification-induced monomer-to-oligomer conversion of PrP from three species using western blotting, circular dichroism, size-exclusion chromatography, and resistance to proteinase K (PK) digestion. We have further shown that all of the resulting ß-oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, whereas the corresponding monomeric PrP were not toxic. In addition, we found that this toxicity is the result of oligomer-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3 in both wild-type and PrP(-/-) cortical neurons. It is our hope that these results may contribute to our understanding of prion transformation within the brain. We found that ß-state oligomeric PrPs can be generated through protein misfolding cyclic amplification (PMCA) from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP. ß-oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, while the corresponding monomeric PrPs were not toxic. This toxicity is the result of oligomers-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3. These results may contribute to our understanding of prion transformation within the brain.

Inflammasomes-dependent regulation of IL-1ß secretion induced by the virulent Mycobacterium bovis Beijing strain in THP-1 macrophages.

Mycobacterium bovis is the causative agent of tuberculosis in cattle. Infection of macrophages with M. bovis leads to the activation of the "nucleotide binding and oligomerization, leucine-rich repeat and pyrin domains-containing protein 3" (NLRP3) and "absent in melanoma 2" (AIM2) inflammasomes, which in turn triggers release of the proinflammatory cytokine interleukin-1ß (IL-1ß) that contributes to bacterial clearance and plays a crucial role in the host defense. However, NLRP3 and AIM2 inflammasome activation is influenced by several factors and how IL-1ß secretion by M. bovis-infected macrophages is regulated via the inflammasome pathway remains unclear. Here we found that IL-1ß secretion and pro-IL-1ß protein accumulation were inhibited in THP-1 macrophages upon exposure to the virulent M. bovis Beijing strain in the presence of high K(+) concentrations, cycloheximide (a protein synthesis inhibitor) and PR-619 (a deubiquitinating enzyme inhibitor). Scavenging reactive oxygen species (ROS) induced by N-acetylcysteine reduced IL-1ß release independent of the mitochondrial permeability transition. Collectively, our results suggest that IL-1ß secretion by M. bovis-infected THP-1 macrophages is reduced by high extracellular K(+) concentration, inhibition of new protein synthesis, deubiquitination, and ROS generation.

CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer's disease.

Impaired brain glucose uptake and metabolism precede the appearance of clinical symptoms in Alzheimer disease (AD). Neuronal glucose transporter 3 (GLUT3) is decreased in AD brain and correlates with tau pathology. However, what leads to the decreased GLUT3 is yet unknown. In this study, we found that the promoter of human GLUT3 contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2 and CRE3. Overexpression of CRE-binding protein (CREB) or activation of cAMP-dependent protein kinase significantly increased GLUT3 expression. CREB bound to the CREs and promoted luciferase expression driven by human GLUT3-promoter. Among the CREs, CRE2 and CRE3 were required for the promotion of GLUT3 expression. Full-length CREB was decreased and truncation of CREB was increased in AD brain. This truncation was correlated with calpain I activation in human brain. Further study demonstrated that calpain I proteolysed CREB at Gln28-Ala29 and generated a 41-kDa truncated CREB, which had less activity to promote GLUT3 expression. Importantly, human brain GLUT3 was correlated with full-length CREB positively and with activation of calpain I negatively. These findings suggest that overactivation of calpain I caused by calcium overload proteolyses CREB, resulting in a reduction of GLUT3 expression and consequently impairing glucose uptake and metabolism in AD brain.

Downregulation of ß-Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein: Proteomics-Based Identification in Early-Stage Prion Disease.

Prion diseases are known as neurodegenerative diseases of the central nervous system with a long incubation period. Alzheimer's disease (AD) and prion diseases share the hallmark of severe neuronal loss, although their pathogenic mechanisms are similarly incomplete. It appears that these two neurodegenerative diseases share a complex deterioration of function involved in the onset of neuronal loss. To investigate presymptomatic biochemical changes indicative of the initial stage of prion diseases and decipher the pathophysiological mechanisms of these two neurodegenerative diseases, we performed a differential proteomic analysis on brain tissues of 263K-infected hamsters during the presymptomatic period and transgenic APPSWE, PSEN1dE9 mice (a mouse model of AD). We identified 7 differentially expressed proteins including the ß-soluble N-ethylmaleimide-sensitive factor attachment protein (ß-SNAP) by 2-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The ß-SNAP expression patterns in the brains of cases and controls were further quantified by Western blotting. ß-SNAP showed an early decrease followed by a progressive depletion. The expression of ß-SNAP was also significantly downregulated in the mouse model of AD. ß-SNAP is brain-specific and known to bind to the SNAP receptors and is therefore involved in the control of neurotransmitter release as well as in constitutive vesicular transport. Our results suggest that presynaptic failure and abnormalities in neurotransmission may be early events in the development of neuronal dysfunction.

Prokaryotic expression and functional analysis of the Mb1514 gene in Mycobacterium bovis.

The ability of mycobacteria to grow and invade target tissues is the key component in the process of Mycobacterium bovis infection. Therefore, analysis of the proteins responsible for cell invasion will assist clinicians in combating bovine tuberculosis. The Mb1514 gene of M. bovis encodes a hypothetical invasion protein (designated here as MbINV protein), whose function has not yet been directly identified. In this study, the Mb1514 gene from M. bovis was cloned, and expressed in E. coli. The recombinant MbINV protein (a single band of approximately 28 kDa) was purified for biological analysis. Our data demonstrated that recombinant MbINV protein significantly inhibited the viability of RAW264.7 macrophages in a dose-dependent manner (P < 0.05), and induced cell necrosis, indicating that the protein is toxic. MbINV protein infection significantly enhanced the mRNA expression levels of TNF-α, IL-1ß, and NOS2 (P < 0.01), suggesting that MbINV protein may be one of the virulence factors which directly interact with macrophages and modulate the host immune response to M. bovis. An invasion inhibition assay showed that MbINV-inhibited M. bovis invasion of RAW264.7 cells in a concentration-dependant manner, demonstrating it is an invasion protein.

the AIM2 inflammasome is involved in macrophage activation during infection with virulent Mycobacterium bovis strain.

BACKGROUND: Mycobacterium bovis, the causative agent of bovine tuberculosis, infects host macrophages and triggers production of the proinflammatory cytokine interleukin 1ß (IL-1ß). The mechanism by which macrophages become activated and secrete IL-1ß in tuberculosis has not yet been elucidated. METHODS: In this study, we investigated the role of the absence in melanoma 2 (AIM2) inflammasome in IL-1ß release from macrophages infected with pathogenic M. bovis strain. RESULTS: We found that the AIM2 inflammasome activation is involved in the production of IL-1ß in primary and immortalized mouse macrophage upon M. bovis infection; that the activation process requires cytoplasmic potassium efflux, mycobacterial internalization, but not reactive oxygen species (ROS) or IFN-ß release; that the AIM2 inflammasome contributes to the synthesis of proinflammatory and chemotatic factors in M. bovis-infected macrophages; and that the activation of the AIM2 inflammasome is due, at least in part, to mycobacterial translocation into the cytosol. CONCLUSIONS: We conclude that the AIM2 inflammasome is involved in macrophage activation during infection with virulent M. bovis strain. To our knowledge, this is the first evidences for the involvement of the AIM2 inflammasome in M. bovis infection.

Circular design strategies and economic sustainability of construction projects in china: the mediating role of organizational culture.

This research aims to elucidate the relationship between circular design strategies (CDS) and the economic sustainability of construction projects (ESCP), examining the mediating role of organizational culture (OC). Motivated by the imperative to develop a sustainable circular economy (CE) model in the building industry, our study focuses on a crucial dimension of CE processes. Specifically, we investigate how construction firms' organizational values shape their pursuit of desired economic outcomes within CE theory. Through a comprehensive analysis of 359 responses from a cross-sectional survey of Chinese construction firms employing Partial Least Squares-Structural Equation Modeling (PLS-SEM), our findings reveal a positive albeit weakly impactful association between CDS and ESCP. Simultaneously, OC is identified as a factor detrimental to ESCP. Notably, this study unveils the influential roles of hierarchical culture (HC) and group culture (GC) in shaping the current state of ESCP in China. Emphasizing the significance of CDS, we propose that contract administrators proactively reposition their organizations to adopt strategies conducive to achieving the necessary economic output for construction projects. The originality aspect lies in this research contributes to the existing body of knowledge by offering empirical insights into the theoretical framework, marking the first such empirical study in northern China. We conclude by critically examining research outcomes and limitations while providing insightful recommendations for future research to foster sustainable construction practices in the Chinese context.

Cribriform-morular Thyroid Carcinoma Arising in a Medulloblastoma Survivor: Two Metachronous Tumors Shared with the Activation of the Wnt Signaling Pathway.

Wnt signaling pathway activation is involved in the pathogenesis of a series of malignant tumors and is characterized by the nuclear accumulation of ß-catenin protein. The occurrence of two or more Wnt pathway-associated tumors in a single individual is uncommon and generally attributed to inherited cancer syndrome, especially familial adenomatous polyposis (FAP). Herein, we presented a rare case of a child who suffered from the occurrence of Wnt-activated medulloblastoma and cribriform-morular thyroid carcinoma (CMTC) within a 9-year interval. She had no history of FAP and harbored an unexpected somatic mutation of the APC gene in the CMTC tumor. The potential agents involved in the pathogenesis of the two molecular-linked tumors other than FAP were discussed in this report.

Rapid Immunohistochemistry Based on Ultrasonic Thermal Steam Heating for Improvement of Intraoperative Diagnosis.

OBJECTIVES: To evaluate the role of rapid immunohistochemistry (RIHC) based on ultrasonic thermal steam heating in improving diagnostic accuracy of intraoperative frozen section diagnosis and to recommend RIHC antibody panels for pathologic differential diagnosis. MATERIALS AND METHODS: RIHC based on ultrasonic thermal steam heating was tested for intraoperative frozen diagnosis with difficulty in diagnosis, and all slides were reviewed and compared with the final diagnosis. Ninety-three cases of surgical specimens involving RIHC examination were studied. Discordance rates with paraffin immunohistochemistry were calculated. RESULTS: In 93 cases where RIHC was performed, 85 cases (91%) were proven to be helpful for the diagnosis. A total of 58 antibodies were used for RIHC 276 times, of which 19 antibodies were not effective 25 times. Fifteen RIHC antibody panels are recommended based on staining stability and utilization frequency. CONCLUSION: After improving the staining method, ultrasonic thermal steam heating RIHC is practical, convenient, and cost-effective, making it suitable for use in any pathology department with routine immunohistochemistry reagents. It plays an important auxiliary role in improving the accuracy of intraoperative rapid pathologic diagnosis.

Unveiling the impact of CDK8 on tumor progression: mechanisms and therapeutic strategies.

CDK8 is an important member of the cyclin-dependent kinase family associated with transcription and acts as a key "molecular switch" in the Mediator complex. CDK8 regulates gene expression by phosphorylating transcription factors and can control the transcription process through Mediator complex. Previous studies confirmed that CDK8 is an important oncogenic factor, making it a potential tumor biomarker and a promising target for tumor therapy. However, CDK8 has also been confirmed to be a tumor suppressor, indicating that it not only promotes the development of tumors but may also be involved in tumor suppression. Therefore, the dual role of CDK8 in the process of tumor development is worth further exploration and summary. This comprehensive review delves into the intricate involvement of CDK8 in transcription-related processes, as well as its role in signaling pathways related to tumorigenesis, with a focus on its critical part in driving cancer progression.

CircMYBL2 facilitates hepatocellular carcinoma progression by regulating E2F1 expression.

Circular RNAs (circRNAs) have been recognized as pivotal regulators in tumorigenesis, yet the biological functions as well as molecular mechanisms of the majority of circRNAs in hepatocellular carcinoma (HCC) remain elusive. We sought to unveil the expression profile and biological role of circMYBL2 in HCC. Initial microarray analyses were conducted to probe the expression profile of circMYBL2 in HCC cells, and qRT‒PCR analysis was then performed in HCC cell lines and tissues, revealing significant upregulation of circMYBL2. Subsequent experiments were conducted to evaluate the biological function of circMYBL2 in HCC progression. Furthermore, bioinformatics analysis, qRT‒PCR analysis, luciferase reporter assays, and western blot analysis were employed to investigate the interplay among circMYBL2, miR-1205, and E2F1. CircMYBL2 was found to exhibit marked upregulation in tumor tissues as well as HCC cell lines. Elevated expression of circMYBL2 increased the proliferation and migration of HCC cells, whereas circMYBL2 knockdown elicited contrasting effects. Mechanistically, our results indicated that circMYBL2 promoted E2F1 expression and facilitated HCC progression by sponging miR-1205. Our findings revealed that circMYBL2 contributed to HCC progression through the circMYBL2/miR-1205/E2F1 axis, suggesting the potential of circMYBL2 as a novel target for HCC treatment or a prognostic biomarker for HCC.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10 inclusion.

Tau exon 10, which encodes the second microtubule-binding repeat, is regulated by alternative splicing. Its alternative splicing generates Tau isoforms with three- or four-microtubule-binding repeats, named 3R-tau and 4R-tau. Adult human brain expresses equal levels of 3R-tau and 4R-tau. Imbalance of 3R-tau and 4R-tau causes Tau aggregation and neurofibrillary degeneration. In the present study, we found that splicing factor SRp55 (serine/arginine-rich protein 55) promoted Tau exon 10 inclusion. Knockdown of SRp55 significantly promoted Tau exon 10 exclusion. The promotion of Tau exon 10 inclusion by SRp55 required the arginine/serine-rich region, which was responsible for the subnucleic speckle localization. Dyrk1A (dual specificity tyrosine-phosphorylated and regulated kinase 1A) interacted with SRp55 and mainly phosphorylated its proline-rich domain. Phosphorylation of SRp55 by Dyrk1A suppressed its ability to promote Tau exon 10 inclusion. Up-regulation of Dyrk1A as in Down syndrome could lead to neurofibrillary degeneration by shifting the alternative splicing of Tau exon 10 to an increase in the ratio of 3R-tau/4R-tau.

Prion protein participates in the regulation of classical and alternative activation of BV2 microglia.

The cellular prion protein (PrP(C) ) is a glycoprotein anchored by glycosylphosphatidylinositol (GPI) to the cell surface and is abundantly expressed in the central nervous system. Numerous studies have suggested a protective function for PrP(C) , including protection from ischemic and excitotoxic lesions and several apoptotic insults, and recent reports have shown that PrP(C) has a context-dependent neuroprotective function. In this study, we investigated the effect of PPNP down-regulation on various forms of microglial activation. We first examined the mRNA expression of PRNP upon exposure to IFN-γ, IL-4, or IL-10 in BV2 microglia. We then analyzed the effect of si-RNA-mediated disruption of PRNP on different parameters of microglial activation in IFN-γ-, IL-4-, or IL-10-stimulated microglia. The results showed that PRNP mRNA expression was invariably down-regulated in microglia upon exposure to IFN-γ, IL-4, or IL-10. PRNP silencing prior to cytokines treatment reduced the responsiveness of microglia to INF-γ treatment, significantly altered IL-4-induced microglial activation phenotype, and had no effect on IL-10-induced microglial activation. Together, these results support a role of PrP(C) in the modulation of the shift of microglia from a quiescent state to an activated phenotype and in the regulation of the microglial response during classical and alternative activation.

Inhibition of phagocytosis reduced the classical activation of BV2 microglia induced by amyloidogenic fragments of beta-amyloid and prion proteins.

The inflammatory responses in Alzheimer's disease and prion diseases are dominated by microglia activation. Three different phenotypes of microglial activation, namely classical activation, alternative activation, and acquired deactivation, have been described. In this study, we investigated the effect of amyloidogenic fragments of amyloid ß and prion proteins (Aß1-42 and PrP106-126) on various forms of microglial activation. We first examined the effect of Aß1-42 and PrP106-126 stimulation on the mRNA expression levels of several markers of microglial activation, as well as the effect of cytochalasin D, a phagocytosis inhibitor, on microglial activation in Aß1-42- and PrP106-126-stimulated BV2 microglia. results showed that Aß1-42 and PrP106-126 induced the classical activation of BV2 microglia, decreased the expression level of alternative expression markers, and had no effect on the expression of acquired deactivation markers. Cytochalasin D treatment significantly reduced Aß1-42- and PrP106-126-induced up-regulation of proinflammatory factors, but did not change the expression profile of the markers of alternative activation or acquired deactivation in BV2 cells which were exposed to Aß1-42 and PrP106-126. Our results suggested that microglia interact with amyloidogenic peptides in the extracellular milieu-stimulated microglial classical activation and reduce its alternative activation, and that the uptake of amyloidogenic peptides from the extracellular milieu amplifies the classical microglial activation.