Histological and Memory Alterations in an Innovative Alzheimer's Disease Animal Model by Vanadium Pentoxide Inhalation.

Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.

Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein.

The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SPs), which are composed of amyloid ß protein (Aß), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 µM CQ had no effect on cell viability; however, 100 µM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

Multifaceted Alzheimer's Disease: Building a Roadmap for Advancement of Novel Therapies.

Alzheimer's disease (AD) is one of the most prevailing neurodegenerative disorders of elderly humans associated with cognitive damage. Biochemical, epigenetic, and pathophysiological factors all consider a critical role of extracellular amyloid-beta (Aß) plaques and intracellular neurofibrillary tangles (NFTs) as pathological hallmarks of AD. In an endeavor to describe the intricacy and multifaceted nature of AD, several hypotheses based on the roles of Aß accumulation, tau hyperphosphorylation, impaired cholinergic signaling, neuroinflammation, and autophagy during the initiation and advancement of the disease have been suggested. However, in no way do these theories have the potential of autonomously describing the pathophysiological alterations located in AD. The complex pathological nature of AD has hindered the recognition and authentication of successful biomarkers for the progression of its diagnosis and therapeutic strategies. There has been a significant research effort to design multi-target-directed ligands for the treatment of AD, an approach which is developed by the knowledge that AD is a composite and multifaceted disease linked with several separate but integrated molecular pathways.

Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer's Disease Hallmarks in SAMP8 Mice.

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.

Defective Autophagy and Mitophagy in Alzheimer's Disease: Mechanisms and Translational Implications.

The main histopathology of Alzheimer's disease (AD) is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aß plaques, and hence stops the neurodegenerative course in AD.

Identification of ortho catechol-containing isoflavone as a privileged scaffold that directly prevents the aggregation of both amyloid ß plaques and tau-mediated neurofibrillary tangles and its in vivo evaluation.

In this study, polyhydroxyisoflavones that directly prevent the aggregation of both amyloid ß (Aß) and tau were expediently synthesized via divergent Pd(0)-catalyzed Suzuki-Miyaura coupling and then biologically evaluated. By preliminary structure-activity relationship studies using thioflavin T (ThT) assays, an ortho-catechol containing isoflavone scaffold was proven to be crucial for preventing both Aß aggregation and tau-mediated neurofibrillary tangle formation. Additional TEM experiment confirmed that ortho-catechol containing isoflavone 4d significantly prevented the aggregation of both Aß and tau. To investigate the mode of action (MOA) of 4d, which possesses an ortho-catechol moiety, 1H-15N HSQC NMR analysis was thoroughly performed and the result indicated that 4d could directly inhibit both the formation of Aß42 fibrils and the formation of tau-derived neurofibrils, probably through the catechol-mediated nucleation of tau. Finally, 4d was demonstrated to alleviate cognitive impairment and pathologies related to Alzheimer's disease in a 5XFAD transgenic mouse model.

Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3ß and inhibiting Tau hyperphosphorylation.

Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3ß (GSK3ß). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.

Estrogen Protects Optic Nerve Head Astrocytes Against Oxidative Stress by Preventing Caspase-3 Activation, Tau Dephosphorylation at Ser422 and the Formation of Tau Protein Aggregates.

Glaucoma is a neurodegenerative disorder that leads to the slow degeneration of retinal ganglion cells, and results in damage to the optic nerve and concomitant vision loss. As in other disorders affecting the viability of central nervous system neurons, neurons affected by glaucoma do not have the ability to regenerate after injury. Recent studies indicate a critical role for optic nerve head astrocytes (ONHAs) in this process of retinal ganglion cell degeneration. Cleavage of tau, a microtubule stabilizing protein and constituent of neurofibrillary tangles (NFT), plays a major part in the mechanisms that lead to toxicity in CNS neurons and astrocytes. Here, we tested the hypothesis that estrogen, a pleiotropic neuro- and cytoprotectant with high efficacy in the CNS, prevents tau cleavage, and hence, protects ONHAs against cell damage caused by oxidative stress. Our results indicate that estrogen prevents caspase-3 mediated tau cleavage, and thereby decreases the levels of the resulting form of proteolytically cleaved tau protein, which leads to a decrease in NFT formation, which requires proteolytically cleaved tau protein. Overall, our data propose that by stopping the reduction of estrogen levels involved with aging the sensitivity of the optic nerve to glaucomatous damage might be reduced. Furthermore, our data suggest that therapeutic use of estrogen may be beneficial in slowing or preventing the onset or severity of neurodegenerative diseases such as glaucoma and potentially also other degenerative diseases of the CNS through direct control of posttranslational modifications of tau protein.

Purines and Pyrimidines: Metabolism, Function and Potential as Therapeutic Options in Neurodegenerative Diseases.

Various neurodegenerative disorders have various molecular origins but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer's Disease.

One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer's disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics' pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, ß-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence.

Pharmacological Treatment of Alzheimer's Disease: Insights from Drosophila melanogaster.

Aging is an ineluctable law of life. During the process of aging, the occurrence of neurodegenerative disorders is prevalent in the elderly population and the predominant type of dementia is Alzheimer's disease (AD). The clinical symptoms of AD include progressive memory loss and impairment of cognitive functions that interfere with daily life activities. The predominant neuropathological features in AD are extracellular ß-amyloid (Aß) plaque deposition and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Because of its complex pathobiology, some tangible treatment can only ameliorate the symptoms, but not prevent the disease altogether. Numerous drugs during pre-clinical or clinical studies have shown no positive effect on the disease outcome. Therefore, understanding the basic pathophysiological mechanism of AD is imperative for the rational design of drugs that can be used to prevent this disease. Drosophila melanogaster has emerged as a highly efficient model system to explore the pathogenesis and treatment of AD. In this review we have summarized recent advancements in the pharmacological research on AD using Drosophila as a model species, discussed feasible treatment strategies and provided further reference for the mechanistic study and treatment of age-related AD.

Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer's Disease.

Alzheimer's Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

Insights from Drosophila melanogaster model of Alzheimer's disease.

Alzheimer's disease (AD) is a common chronic neurodegenerative disease that mainly affects the medial temporal lobe and associated neocortical structures. The disease process involves two abnormal structures, plaques and tangles, which damage and destroy nerve cells. Tangles are twisted fibers of tau protein that build up inside cells. Plaques are deposits of a protein fragment called amyloid-beta (Aß) that accumulate in the spaces between nerve cells. Aß derives from the amyloid precursor protein and is the main component of amyloid plaques in the AD brain. Although AD has been extensively examined, its pathogenetic mechanisms remain unclear and there are currently no effective drugs for this disorder. Many AD model systems have recently been established using Drosophila melanogaster by expressing the proteins involved in AD in the brain. These systems successfully reflect some of the symptoms associated with AD such as the onset of learning defects, age-dependent short-term memory impairment, increase of wakefulness and consolidated sleep disruption by expressing human Aß42 or human APP/BACE in Drosophila central nervous system. We herein discuss these Drosophila AD models.

Neuro-amelioration of cinnamaldehyde in aluminum-induced Alzheimer's disease rat model.

Aluminum (Al) is a neurotoxic substance which has played an important role in the etiology, pathogenesis, and development of amyloid-ß (Aß) plaques. This study was carried out to evaluate the neuroprotective effect of aqueous cinnamon extract against aluminum chloride (AlCl3)-induced Alzheimer's disease. Forty adult male albino rats, randomly divided into four equal groups. Control group; ACE200 group administered aqueous cinnamon extract (ACE) orally; AlCl3 group received daily intraperitoneal (i.p.) injection of AlCl3 for 60 days to induce neurotoxicity and AlCl3 + ACE200 group received a combination of AlCl3 and ACE in the same dose and route as previous groups. Aluminum administration significantly enhanced the memory impairment and the Aß formation in the rat model. The cerebellum exhibited a significant reduced number of Purkinje cells, marked decrease in the density of dendritic arborization and prominent perineuronal spaces in the molecular layer. There was loss of dendritic spines, neurofibrillary degeneration, and appearance of neuritic plaques. Concomitant administration of AlCl3 and ACE displayed an observable protection against these changes with progressive improvement in memory and intellectual performance. In conclusion, ACE may play a protective role against formation of amyloid-ß plaques in cerebellum.

Transition metal nickel prevents Tau aggregation in Alzheimer's disease.

Alzheimer's disease is the leading cause of dementia, effecting majority of aged people worldwide. The multifaceted effectors of Alzheimer's disease primarily include Tau, amyloid-ß along with hyper activation of kinases, oxidative stress and mutations etc., makes it challenging to design therapeutics. Tau is a microtubule-associating protein, which is subjected to cellular stress resulting in the formation of neurofibrillary tangles, leading to loss of affinity for microtubules. This causes loss of microtubule stability and in turn alters axonal integrity. In the present work, emphasis towards understanding interaction of nickel with Tau was made. Metals such as iron, zinc, copper and lead etc., are known to modulate Tau conformation and enhance its aggregation. Our results showed the deliverance of Tau aggregation by nickel and its synthetic morpholine conjugate. Nickel prevents aggregation by inducing degradation of Tau as evidenced by SDS-PAGE and TEM. Nickel and the synthetic conjugate being non-toxic to neuro2a cells and prevent Tau aggregation, might direct these complexes to overcome AD.

Regional differences in Alzheimer's disease pathology confound behavioural rescue after amyloid-ß attenuation.

Failure of Alzheimer's disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer's disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-ß peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-ß peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-ß peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-ß peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-ß, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

Early insight into the potential contribution of aluminum to neurodegeneration - A tribute to the research work of Robert D. Terry, Igor Klatzo, Henryk M. Wisniewski and Donald R.C. Mclachlan.

The first successful attempt to obtain purified aluminum metal was accomplished by the Danish physicist and chemist Hans Christian Orsted in 1824, however it was not until about ~140 years later that aluminum's capacity for neurological disruption and neurotoxicity was convincingly established. The earliest evidence of the possible involvement of this biosphere-rich metallotoxin in Alzheimer's disease (AD) originated in the early-to-mid-1960's from animal and human research investigations that arose almost simultaneously from independent laboratories in the United States and Canada. This short communication pays tribute to the pioneering research work on aluminum in susceptible species, in AD animal models and in AD patients by the early investigators Drs. Robert D. Terry, Igor Klatzo and Henryk M. Wisniewski with special acknowledgement to the late Dr. Donald RC McLachlan, and their contemporary physician-scientist colleagues and collaborators. Together these researchers established the groundwork and foundation towards our understanding of the potential contribution of aluminum to progressive, age-related and lethal neurodegenerative diseases of the human central nervous system.

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau.

BACKGROUND: Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer's disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study. METHODS: Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings. RESULTS: Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex - 53%, p < 0.001; hippocampus - 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001). CONCLUSION: Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.

Small-molecule drug screening identifies drug Ro 31-8220 that reduces toxic phosphorylated tau in Drosophila melanogaster.

The intraneuronal aggregates of hyperphosphorylated and misfolded tau (neurofibrillary tangles, NFTs) cause a stereotypical spatiotemporal Alzheimer's disease (AD) progression that correlates with the severity of the associated cognitive decline. Kinase activity contributes to the balance between neuron survival and cell death. Hyperactivation of kinases including the conventional protein kinase C (PKC) is a defective molecular event accompanying associative memory loss, tau phosphorylation, and progression of AD or related neurodegenerative diseases. Here, we investigated the ability of small therapeutic compounds (a custom library) to improve tau-induced rough-eye phenotype in a Drosophila melanogaster model of frontotemporal dementia. We also assessed the tau phosphorylation in vivo and selected hit compounds. Among the potential hits, we investigated Ro 31-8220, described earlier as a potent PKCα inhibitor. Ro 31-8220 robustly improved the rough-eye phenotype, reduced phosphorylated tau species in vitro and in vivo, reversed tau-induced memory impairment, and improved the fly motor functions. In a human neuroblastoma cell line, Ro 31-8220 reduced the PKC activity and the tau phosphorylation pattern, but we also have to acknowledge the compound's wide range of biological activity. Nevertheless, Ro 31-8220 is a novel therapeutic mitigator of tau-induced neurotoxocity.