Aversive conditioning information transmission in Drosophila.

Animals rapidly acquire surrounding information to perform the appropriate behavior. Although social learning is more efficient and accessible than self-learning for animals, the detailed regulatory mechanism of social learning remains unknown, mainly because of the complicated information transfer between animals, especially for aversive conditioning information transmission. The current study revealed that, during social learning, the neural circuit in observer flies used to process acquired aversive conditioning information from demonstrator flies differs from the circuit used for self-learned classic aversive conditioning. This aversive information transfer is species dependent. Solitary flies cannot learn this information through social learning, suggesting that this ability is not an innate behavior. Neurons used to process and execute avoidance behavior to escape from electrically shocked flies are all in the same brain region, indicating that the fly brain has a common center for integrating external stimuli with internal states to generate flight behavior.

Early Aß42 Exposure Causes Learning Impairment in Later Life.

Amyloid cascade hypothesis proposes that amyloid ß (Aß) accumulation is the initiator and major contributor to the development of Alzheimer's disease (AD). However, this hypothesis has recently been challenged by clinical studies showing that reduction of Aß accumulation in the brain does not accompany with cognitive improvement, suggesting that therapeutically targeting Aß in the brain may not be sufficient for restoring cognitive function. Since the molecular mechanism underlying the progressive development of cognitive impairment after Aß clearance is largely unknown, the reason of why there is no behavioral improvement after Aß clearance remains elusive. In the current study, we demonstrated that transient Aß expression caused learning deficit in later life, despite the accumulated Aß was soon being removed after the expression. Early Aß exposure decreased the cellular expression of XBP1 and both the antioxidants, catalase, and dPrx5, which made cells more vulnerable to oxidative stress in later life. Early induction of XBP1, catalase, and dPrx5 prevented the overproduction of ROS, improved the learning performance, and preserved the viability of cells in the later life with the early Aß induction. Treating the early Aß exposed flies with antioxidants such as vitamin E, melatonin and lipoic acid, after the removal of Aß also preserved the learning ability in later life. Taken together, we demonstrated that early and transient Aß exposure can have a profound impact on animal behavior in later life and also revealed the cellular and molecular mechanism underlying the development of learning impairment by the early and transient Aß exposure.

Disrupted cellular calcium homeostasis is responsible for Aß-induced learning and memory damage and lifespan shortening in a model of Aß transgenic fly.

Accumulated Aß is one of the hallmarks of Alzheimer's disease. Although accumulated results from in vivo and in vitro studies have shown that accumulated Aß causes learning and memory deficit, cell death, and lifespan reduction, the underlying mechanism remains elusive. In neurons, calcium dynamics is regulated by voltage-gated calcium channel (VGCC) and endoplasmic reticulum and is important for neuron survival and formation of learning and memory. The current study employs in vivo genetics to reveal the role of calcium regulation systems in Aß-induced behavioral damage. Our data shows that although increased VGCC improves learning and memory in Aß42 flies, reduction of VGCC and Inositol trisphosphate receptors extends Aß42 flies' lifespan and improves cell viability. The complex role of calcium regulation systems in Aß-induced damage suggests that the imbalance of calcium dynamic is one of the main factors to trigger learning and memory deficit and cell death in the disease.

The double-edged sword effect of HDAC6 in Aß toxicities.

Alzheimer's disease (AD) is marked by cognitive impairment, massive cell death, and reduced life expectancy. Pathologically, accumulated beta-amyloid (Aß) aggregates and hyperphosphorylated tau protein is the hallmark of the disease. Although changes in cellular function and protein accumulates have been demonstrated in many different AD animal models, the molecular mechanism involved in different cellular functions and the correlation and causative relation between different protein accumulations remain elusive. Our in vivo genetic studies revealed that the molecular mechanisms involved in memory loss and lifespan shortening are different and that tau plays an essential role in mediating Aß-induced early death. We found that when the first deacetylase (DAC) domain of histone deacetylase 6 (HDAC6) activity was increased, it regulated cortactin deacetylation to reverse Aß-induced learning and memory deficit, but with no effect on the lifespan of the Aß flies. On the other hand, an increased amount of the second DAC domain of HDAC6 promoted tau phosphorylation to facilitate Aß-induced lifespan shortening without affecting learning performance in the Aß flies. Our data also confirmed decreased acetylation in two major HDAC6 downstream proteins, suggesting increased HDAC6 activity in Aß flies. Our data established the double-edged sword effect of HDAC6 activity in Aß-induced pathologies. Not only did we segregate memory loss and lifespan shortening in Aß flies, but we also provided evidence to link the Aß with tau signaling.

Rac1 and Akt Exhibit Distinct Roles in Mediating Aß-Induced Memory Damage and Learning Impairment.

Accumulated beta-amyloid (Aß) in the brain is the hallmark of Alzheimer's disease (AD). Despite Aß accumulation is known to trigger cellular dysfunctions and learning and memory damage, the detailed molecular mechanism remains elusive. Recent studies have shown that the onset of memory impairment and learning damage in the AD animal is different, suggesting that the underlying mechanism of the development of memory impairment and learning damage may not be the same. In the current study, with the use of Aß42 transgenic flies as models, we found that Aß induces memory damage and learning impairment via differential molecular signaling pathways. In early stage, Aß activates both Ras and PI3K to regulate Rac1 activity, which affects mostly on memory performance. In later stage, PI3K-Akt is strongly activated by Aß, which leads to learning damage. Moreover, reduced Akt, but not Rac1, activity promotes cell viability in the Aß42 transgenic flies, indicating that Akt and Rac1 exhibit differential roles in Aß regulating toxicity. Taken together, different molecular and cellular mechanisms are involved in Aß-induced learning damage and memory decline; thus, caution should be taken during the development of therapeutic intervention in the future.

Aging-induced Akt activation involves in aging-related pathologies and Aß-induced toxicity.

Multicellular signals are altered in the processes of both aging and neurodegenerative diseases, including Alzheimer's disease (AD). Similarities in behavioral and cellular functional changes suggest a common regulator between aging and AD that remains undetermined. Our genetics and behavioral approaches revealed the regulatory role of Akt in both aging and AD pathogenesis. In this study, we found that the activity of Akt is upregulated during aging through epidermal growth factor receptor activation by using the fruit fly as an in vivo model. Downregulation of Akt in neurons improved cell survival, locomotor activity, and starvation challenge in both aged and Aß42-expressing flies. Interestingly, increased cAMP levels attenuated both Akt activation-induced early death and Aß42-induced learning deficit in flies. At the molecular level, overexpression of Akt promoted Notch cleavage, suggesting that Akt is an endogenous activity regulator of γ-secretase. Taken together, this study revealed that Akt is involved in the aging process and Aß toxicity, and manipulating Akt can restore both neuronal functions and improve behavioral activity during the processes of aging and AD pathogenesis.

XBP1 and PERK Have Distinct Roles in Aß-Induced Pathology.

Endoplasmic reticulum (ER) stress triggers multiple cellular signals to restore cellular function or induce proapoptosis that is altered in the brains of patients with Alzheimer's disease (AD). However, the role of ER stress in ß-amyloid (Aß)-induced AD pathology remains elusive, and data obtained from different animal models and under different experimental conditions are sometimes controversial. The current study conducted in vivo genetic experiments to systematically examine the distinct role of each ER stress effector during disease progression. Our results indicated that inositol-requiring enzyme 1 was activated before protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation in Aß42 transgenic flies. Proteasome activity played a key role in this sequential activation. Furthermore, our study separated learning deficits from early degeneration in Aß-induced impairment by demonstrating that X-box binding protein 1 overexpression at an early stage reversed Aß-induced early death without affecting learning performance in the Aß42 transgenic flies. PERK activation was determined to only enhance Aß-induced learning deficits. Moreover, proteasome overactivation was determined to delay PERK activation and improve learning deficits. Altogether, the findings of this study demonstrate the complex roles of ER stress during Aß pathogenesis and the possibility of using different ER stress effectors as reporters to indicate the status of disease progression.

Dysfunction of different cellular degradation pathways contributes to specific ß-amyloid42-induced pathologies.

The endosomal-lysosomal system (ELS), autophagy, and ubiquitin-proteasome system (UPS) are cellular degradation pathways that each play a critical role in the removal of misfolded proteins and the prevention of the accumulation of abnormal proteins. Recent studies on Alzheimer's disease (AD) pathogenesis have suggested that accumulation of aggregated ß-amyloid (Aß) peptides in the AD brain results from a dysfunction in these cellular clearance systems. However, the specific roles of these pathways in the removal of Aß peptides and the pathogenesis underlying AD are unclear. Our in vitro and in vivo genetic approaches revealed that ELS mainly removed monomeric ß-amyloid42 (Aß42), while autophagy and UPS clear oligomeric Aß42. Although overproduction of phosphatidylinositol 4-phosphate-5 increased Aß42 clearance, it reduced the life span of Aß42 transgenic flies. Our behavioral studies further demonstrated impaired autophagy and UPS-enhanced Aß42-induced learning and memory deficits, but there was no effect on Aß42-induced reduction in life span. Results from genetic fluorescence imaging showed that these pathways were damaged in the following order: UPS, autophagy, and finally ELS. The results of our study demonstrate that different degradation pathways play distinct roles in the removal of Aß42 aggregates and in disease progression. These findings also suggest that pharmacologic treatments that are designed to stimulate cellular degradation pathways in patients with AD should be used with caution.-Ji, X.-R., Cheng, K.-C., Chen, Y.-R., Lin, T.-Y., Cheung, C. H. A., Wu, C.-L., Chiang, H.-C. Dysfunction of different cellular degradation pathways contributes to specific ß-amyloid42-induced pathologies.