Trade-offs between bycatch and target catches in static versus dynamic fishery closures.

While there have been recent improvements in reducing bycatch in many fisheries, bycatch remains a threat for numerous species around the globe. Static spatial and temporal closures are used in many places as a tool to reduce bycatch. However, their effectiveness in achieving this goal is uncertain, particularly for highly mobile species. We evaluated evidence for the effects of temporal, static, and dynamic area closures on the bycatch and target catch of 15 fisheries around the world. Assuming perfect knowledge of where the catch and bycatch occurs and a closure of 30% of the fishing area, we found that dynamic area closures could reduce bycatch by an average of 57% without sacrificing catch of target species, compared to 16% reductions in bycatch achievable by static closures. The degree of bycatch reduction achievable for a certain quantity of target catch was related to the correlation in space and time between target and bycatch species. If the correlation was high, it was harder to find an area to reduce bycatch without sacrificing catch of target species. If the goal of spatial closures is to reduce bycatch, our results suggest that dynamic management provides substantially better outcomes than classic static marine area closures. The use of dynamic ocean management might be difficult to implement and enforce in many regions. Nevertheless, dynamic approaches will be increasingly valuable as climate change drives species and fisheries into new habitats or extended ranges, altering species-fishery interactions and underscoring the need for more responsive and flexible regulatory mechanisms.

An Acoustofluidic Picoinjector.

Droplet microfluidics has emerged as a valuable technology for a multitude of chemical and biomedical applications, offering the capability to create independent microenvironments for high-throughput assays. Central to numerous droplet microfluidic applications is the picoinjection of materials into individual droplets, yet existing picoinjection methods often exhibit high power requirements, lack biocompatibility, and/or suffer from limited controllability. Here, we present an acoustofluidic picoinjector that generates acoustic pressure at the droplet interface to enable on-demand, energy-efficient, and biocompatible injection at high precision. We validate our platform by performing acid-base titrations by iteratively injecting picoliter volume reagents into droplets to induce pH transitions detectable by color change in solution. Additionally, we demonstrate the versatility of the acoustofluidic picoinjector in the synthesis of metallic nanoparticles, yielding highly monodisperse and reproducible particle morphologies compared to conventional bulk-phase techniques. By facilitating controlled delivery of reagents or biological samples with unparalleled accuracy, acoustofluidic picoinjection broadens the utility of droplet microfluidics for a myriad of applications in chemical and biological research.

Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy.

Aquaporin-4 (AQP4) plays a crucial role in brain water circulation and is considered a therapeutic target in hydrocephalus. Congenital hydrocephalus is associated with a reaction of astrocytes in the periventricular white matter both in experimental models and human cases. A previous report showed that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplanted into the lateral ventricles of hyh mice exhibiting severe congenital hydrocephalus are attracted by the periventricular astrocyte reaction, and the cerebral tissue displays recovery. The present investigation aimed to test the effect of BM-MSC treatment on astrocyte reaction formation. BM-MSCs were injected into the lateral ventricles of four-day-old hyh mice, and the periventricular reaction was detected two weeks later. A protein expression analysis of the cerebral tissue differentiated the BM-MSC-treated mice from the controls and revealed effects on neural development. In in vivo and in vitro experiments, BM-MSCs stimulated the generation of periventricular reactive astrocytes overexpressing AQP4 and its regulatory protein kinase D-interacting substrate of 220 kDa (Kidins220). In the cerebral tissue, mRNA overexpression of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF1α), and transforming growth factor beta 1 (TGFß1) could be related to the regulation of the astrocyte reaction and AQP4 expression. In conclusion, BM-MSC treatment in hydrocephalus can stimulate a key developmental process such as the periventricular astrocyte reaction, where AQP4 overexpression could be implicated in tissue recovery.

Pancreatic intraductal papillary mucinous neoplasm evolving into adenocarcinoma. Continual follow-up necessary.

We report a 62-year-old female with chronic pancreatitis after three episodes of severe acute pancreatitis. In 2008, an uneven main pancreatic duct (MPD) of 16 mm was found during an abdominal ultrasound. The follow-up was not continued until 2020, when a dilation of 27 mm of the MPD was discovered at magnetic resonance imaging (MRI). In 2022, another radiological test was carried out showing a dilation of the MPD of 40 mm with an intraductal tumoral lesion of 30 mm at the head of the pancreas). An echo-endoscopy was carried out and a pancreatic-duodenal tumour with a mixed pattern was discovered. Atypic cells were observed at the fine needle punction. A total duodenopancreatectomy was successfully carried out. In the anatomopathological macroscopic study a 14 cm-multi-cystic neoformation was seen and a solid tumour was discovered at the head of the pancreas that infiltrated the wall of the duodenum. In the longitudinal cross-section of the pancreatic body the MPD was seen to be severely dilated. A focal adenocarcinoma in a intraductal papillary mucinous neoplasm (IPMN) was finally diagnosed. Pancreatic lesions are usually asymptomatic and are detected by chance during other imaging tests. The IPMN rates of malignancy have been reported of between 19 to 30%. The management of pancreatic cystic lesions still represents a clinical challenge. As always, the multi-disciplinary management is mandatory in this type of tumour.

Amyloid-ß impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease.

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid-ß plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid-ß peptides), Tau (containing AT8- and AT100-positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs-APP, but not AT8/AT100-positive SNs-Tau, as compared with SNs-WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12-month-old APP mice, since only 1.60 ± 3.81% of peri-plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia-mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia-dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid-ß alone. Taken together, our data suggest that amyloid-ß, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid-ß, as well as of peri-plaque dystrophic synapses containing amyloid-ß, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer's Disease.

Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer's disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER/Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aß and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aß) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aß plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aß. Gal3 deletion decreased the Aß burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aß monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aß aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2-DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.

Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.

The role of microglial cells in the development and progression of Alzheimer's disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance ("microglial domain"). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.

Expanding the library of divalent fucosidase inhibitors with polyamino and triazole-benzyl bridged bispyrrolidines.

A small library of divalent fucosidase inhibitors containing pyrrolidine motifs and separated by polyamino and triazole-benzylated spacers was prepared and evaluated as α-fucosidase inhibitors. Although a weak multivalent effect was observed in polyamino derived dimers, useful structural information can be deduced about the length of the bridge, the number of nitrogen atoms present and the moieties close to the pyrrolidine. Within these investigations one of the best α-fucosidase inhibitors containing a pyrrolidine framework was obtained (18, Ki = 3.7 nM).

Evidence for a Nest Defense Pheromone in Bald-Faced Hornets, Dolichovespula Maculata, and Identification of Components.

In eusocial insects like Bald-faced hornets, Dolichovespula maculata, nest defense is essential because nests contain a large number of protein-rich larvae and pupae, and thus are attractive to nest predators. Our objectives were to investigate whether D. maculata exhibit pheromone-mediated nest defense, and to identify and field test any pheromone components. We tested for pheromone-mediated nest defense behavior of D. maculata by placing a paired box-apparatus near the entrance of D. maculata nests, and treating both boxes with a solvent control, or one of the two boxes with a solvent control and the other with either venom sac extract, the putative source of nest defense pheromone, or synthetic pheromone. The sound impulses caused by nest mates attempting to sting or strike the boxes were recorded for 3 min. Compared to the double-control treatment, the number of strikes increased 27-fold when one of the two boxes was treated with venom sac extract, providing evidence for an alarm response. The box treated with venom sac extract also induced a significantly greater proportion of strikes than the corresponding control box, providing evidence for a target-oriented response. Analyzing venom sac extract by gas chromatographic-electroantennographic detection (GC-EAD) and GC-mass spectrometry resulted in the identification of seven candidate pheromone components: (a) dimethylaminoethanol, (b) dimethylamino ethyl acetate, (c) 2,5-dimethylpyrazine, (d) N-3-methylbutylacetamide, (e) 2-heptadecanone, (f) (Z)-8-heptadecen-2-one, and (g) (Z)-10-nonadecen-2-one. Testing in paired-box bioassays blends of the nitrogen-containing volatile components a-d, the less volatile ketones e-g, or both (a-g), indicated that a-d primarily have an alarm function. The ketones e-g, in contrast, induced target-oriented responses, possibly marking the box, or potential nest predators, for guided and concerted attacks, or enhancing the alarm-inducing effect of the volatile pheromone components, as shown in honey bees. Comparing the behavioral effects of venom sac extract, blends a-d, e-g, and a-g, venom sac extract was most effective in triggering the full complement of alarm and target-oriented responses. These comparisons further suggested that a component is missing in the group of components that triggers the alarm rather than the target-oriented response.

Increased levels of tumour necrosis factor alpha (TNFα) but not transforming growth factor-beta 1 (TGFß1) are associated with the severity of congenital hydrocephalus in the hyh mouse.

AIMS: Here, we tested the hypothesis that glial responses via the production of cytokines such as transforming growth factor-beta 1 (TGFß1) and tumour necrosis factor alpha (TNFα), which play important roles in neurodegenerative diseases, are correlated with the severity of congenital hydrocephalus in the hyh mouse model. We also searched for evidence of this association in human cases of primary hydrocephalus. METHODS: Hyh mice, which exhibit either severe or compensated long-lasting forms of hydrocephalus, were examined and compared with wild-type mice. TGFß1, TNFα and TNFαR1 mRNA levels were quantified using real-time PCR. TNFα and TNFαR1 were immunolocalized in the brain tissues of hyh mice and four hydrocephalic human foetuses relative to astroglial and microglial reactions. RESULTS: The TGFß1 mRNA levels were not significantly different between hyh mice exhibiting severe or compensated hydrocephalus and normal mice. In contrast, severely hydrocephalic mice exhibited four- and two-fold increases in the mean levels of TNFα and TNFαR1, respectively, compared with normal mice. In the hyh mouse, TNFα and TNFαR1 immunoreactivity was preferentially detected in astrocytes that form a particular periventricular reaction characteristic of hydrocephalus. However, these proteins were rarely detected in microglia, which did not appear to be activated. TNFα immunoreactivity was also detected in the glial reaction in the small group of human foetuses exhibiting hydrocephalus that were examined. CONCLUSIONS: In the hyh mouse model of congenital hydrocephalus, TNFα and TNFαR1 appear to be associated with the severity of the disease, probably mediating the astrocyte reaction, neurodegenerative processes and ischaemia.

The centipedes (Arthropoda, Myriapoda, Chilopoda) from Colombia: Part I. Scutigeromorpha and Scolopendromorpha.

This study presents an updated list of centipedes of the orders Scutigeromorpha and Scolopendromorpha from Colombia based on data from the literature, the World Catalogue of Centipedes (CHILOBASE), and specimens examined in museum collections. Four families, nine genera, 37 species and four subspecies are listed. One species belongs to Scutigeromorpha, and 36 species and four subspecies to Scolopendromorpha. Eleven species and four subspecies of scolopendromorphs are recorded for the first time from Colombia. Newportia Gervais, 1847 is the most diverse genus with 12 species and three subspecies. Six species of Scolopendromorpha are endemic. Three species-Otostigmus inermis Porat, 1876, O. scabricauda (Humbert & Saussure, 1870) and Cryptops iheringi Brölemann, 1902-are deleted from the fauna of Colombia. The Andean Región in Colombia has the most records of Scutigeromorpha and Scolopendromorpha. Maps showing the geographical distribution are given for the orders, genera, and some species.

An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Interspecific variability in plastic ingested by Procellariiformes off the Uruguayan coast.

We assessed the interspecific variability in plastic ingested by albatrosses and petrels using bycaught birds from fisheries of the Southwest Atlantic. From 107 stomachs examined, 4.17 % of the albatrosses and 62.86 % of the petrels contained plastics. Macronectes halli and Ardenna gravis had 100 % of occurrence. They were followed by Procellaria conspicillata (75 %), Procellaria aequinoctialis (47.62 %), T. melanophris (4.35 %) and T. chlororhynchos (0 %). The most common groups of plastics by size, type and color, were mesoplastics (5-20 mm), user plastics and white-clear items, respectively. Larger species tend to ingest larger items with greater surfaces. Together with evidence from other studies, our results indicate that interspecific differences in the occurrence and the dimensions of plastics appear to be associated with digestive tract morphology, foraging techniques, body size, interaction with fishing vessels, and with the availability of plastics at the sea surface.

The Performance Diagnostic Checklist-Human Services (1.1): An initial assessment of validity and reliability.

The Performance Diagnostic Checklist-Human Services (PDC-HS) is an assessment used to identify variables contributing to staff performance concerns in human-service settings. In the current study, we introduce and assess the test validity, interrater reliability, and test-retest reliability of the PDC-HS (1.1), a revised version of the assessment that included revised instructions, questions, and intervention planning references. We measured the psychometric properties of the revised assessment by analyzing answers obtained from watching video vignettes of simulated interviews between consultants and a supervisor. Twenty-one participants watched the vignettes and completed the PDC-HS (1.1) based on the answers provided during the interview. We also included an item analysis to identify questions on which participants made errors and an intervention selection task to assess whether participants selected an appropriate intervention to target the indicated domain. The results support the use of the PDC-HS (1.1) in human services settings.

Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer's disease hippocampus.

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V-VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.

Extended Sentinel Monitoring of Helicoverpa zea Resistance to Cry and Vip3Aa Toxins in Bt Sweet Corn: Assessing Changes in Phenotypic and Allele Frequencies of Resistance.

Transgenic corn and cotton that produce Cry and Vip3Aa toxins derived from Bacillus thuringiensis (Bt) are widely planted in the United States to control lepidopteran pests. The sustainability of these Bt crops is threatened because the corn earworm/bollworm, Helicoverpa zea (Boddie), is evolving a resistance to these toxins. Using Bt sweet corn as a sentinel plant to monitor the evolution of resistance, collaborators established 146 trials in twenty-five states and five Canadian provinces during 2020-2022. The study evaluated overall changes in the phenotypic frequency of resistance (the ratio of larval densities in Bt ears relative to densities in non-Bt ears) in H. zea populations and the range of resistance allele frequencies for Cry1Ab and Vip3Aa. The results revealed a widespread resistance to Cry1Ab, Cry2Ab2, and Cry1A.105 Cry toxins, with higher numbers of larvae surviving in Bt ears than in non-Bt ears at many trial locations. Depending on assumptions about the inheritance of resistance, allele frequencies for Cry1Ab ranged from 0.465 (dominant resistance) to 0.995 (recessive resistance). Although Vip3Aa provided high control efficacy against H. zea, the results show a notable increase in ear damage and a number of surviving older larvae, particularly at southern locations. Assuming recessive resistance, the estimated resistance allele frequencies for Vip3Aa ranged from 0.115 in the Gulf states to 0.032 at more northern locations. These findings indicate that better resistance management practices are urgently needed to sustain efficacy the of corn and cotton that produce Vip3Aa.

Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK-3beta pathway in Alzheimer mouse model.

Neurotrophins, activating the PI3K/Akt signaling pathway, control neuronal survival and plasticity. Alterations in NGF, BDNF, IGF-1, or insulin signaling are implicated in the pathogenesis of Alzheimer disease. We have previously characterized a bigenic PS1×APP transgenic mouse displaying early hippocampal Aß deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble Aß oligomers. We hypothesized that PI3K/Akt/GSK-3ß signaling pathway could be involved in this apparent age-dependent neuroprotective/neurodegenerative status. In fact, our data demonstrated that, as compared with age-matched nontransgenic controls, the Ser-9 phosphorylation of GSK-3ß was increased in the 6-month PS1×APP hippocampus, whereas in aged PS1×APP animals (18 months), GSK-3ß phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-α (sAPPα), the predominant APP-derived fragment in young PS1×APP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3ß activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric Aß forms, present in the soluble fractions of aged PS1×APP mice, inhibited the induced phosphorylation of Akt/GSK-3ß and decreased the neuronal survival. Furthermore, synthetic Aß oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPPα, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3ß signaling pathway through the major neurotrophin receptors. sAPPα stimulated and Aß oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.