Brain tumours: Non-invasive techniques to treat invasive pathologies.

Brain and other central nervous system tumours are cancers of poor prognosis, for which current therapeutic possibilities do not match the expectations regarding a curative objective. If the treatment of central nervous system tumours is so difficult, it is partly due to the blood-brain barrier and the blood-tumour barrier, which need to be crossed to access the tumour. Driven by these insufficient results, more and more techniques and technologies are being explored and are evolving: the progress of surgery and radiotherapy, the growing place of immunotherapies, or the apparition of new non-invasive techniques. The latter are those which interest us here, where promising advances are taking the leap to clinical trials. Nose-to-brain delivery, receptor-mediated transcytosis and micro-bubbles-associated focused ultrasounds are three therapeutic propositions with encouraging results regarding the improvement of drug access to the brain. Even though they might have their share of limits and adverse effects, benefit-risk balance looks promising, and they may appear as new options to treat patients in the future.

Physiologically-based pharmacokinetic models to predict drug exposure during pregnancy.

As pregnant women are constantly exposed to drugs during pregnancy, either to treat long-term conditions or acute illnesses, drug safety is a major concern for the fetus and the mother. Clinical trials are rarely made in this population due to strict regulation and ethical reasons. However, drug pharmacokinetic (PK) parameters vary during pregnancy with an increase in distribution volume, renal clearance and more. In addition, the fetal distribution should be evaluated with the importance of placental diffusion, both active and passive. Therefore, there is a recent interest in the use of physiologically-based pharmacokinetic (PBPK) modeling to characterize these changes and complete the sparse data available on drug PK during pregnancy. Indeed, PBPK models integrate drug physicochemical and physiological parameters corresponding to each compartment of the body to estimate drug concentrations. This review establishes an overview on the current use of PBPK models in drug dosage determination for the pregnant woman, fetal exposure and drug interactions in the fetal compartment.

Pro-inflammatory cytokine secretion induced by amyloid transthyretin in human cardiac fibroblasts.

Extracellular aggregates of wild-type human transthyretin are associated with heart diseases such as wild-type transthyretin (TTR)-derived amyloidosis (ATTR-wt). Due to their strategic location, cardiac fibroblasts act as sentinel cells that sense injury and activate the inflammasome. No studies of the effects of TTR amyloid aggregation on the secretion of inflammatory factors by primary human cardiac fibroblasts (hCFs) have been reported yet. The intracellular internalization of TTR aggregates, which correspond to the early stage of ATTR-wt, were determined using immunofluorescence and Western blotting of cell lysates. A further objective of this study was to analyze the secretion of inflammatory factors by hCFs after analysis of TTR amyloid aggregation using X-MAP® Luminex Assay techniques. We show that TTR aggregates are internalized in hCFs and induce the secretion of both Brain Natriuretic Peptide (BNP) and N-terminal pro B-type Natriuretic Peptide(NT-proBNP). Also, pro-inflammatory mediators such as interleukin-6 (IL-6) and IL-8 are secreted without significant changes in the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In conclusion, these findings suggest that IL-6 and IL-8 play important roles in the development of ATTR-wt, and indicate that IL-6 in particular could be a potentially important therapeutic target in patients with ATTR-wt.

Blue marine therapy: Sea as a trove of natural anticancer drugs.

The great variability of marine habitats and the species that live there allows the development of organisms with unique characteristics. These represent an excellent source of natural compounds and are therefore interesting in the search for new bioactive molecules. In recent years, many marine-based drugs have been commercialized or are currently under investigation, mainly in the treatment of cancer. This mini-review summarizes the marine-based drugs currently marketed and presents a non-exhaustive list of molecules currently in clinical trials, as monotherapy but also in combination with classical anticancer treatments.

Chronic intraperitoneal injection of polyethylene glycol 200 in mice induces hippocampal neuroinflammation.

In vivo treatment of hydrophobic substances requires the use of organic solvents, which are often toxic. Consequently, polyethylene glycols (PEGs), which are considered as nontoxic, have been widely used for many years in chemistry and biology. We used PEG 200, which was administrated by intraperitoneal (i.p.) injection once a week to mice. After 4 months of injections, at the dose of 1.67 mL/kg, a surprising increase in expression of GFAP (glial fibrillary acidic protein) and IBA1 (ionized calcium binding adaptor molecule 1), glial markers of astrocytes and microglia respectively, was observed in the mice's hippocampus. These results were associated with a dramatic increase in pro-inflammatory cytokine interleukin-1ß (IL-1ß) expression, all together suggesting an inflammatory process. It is important to communicate these results to the scientific community to provide awareness of this potential effect when PEG 200 is used under similar conditions as a vehicle in mice.

Trans ε-viniferin is an amyloid-ß disaggregating and anti-inflammatory drug in a mouse primary cellular model of Alzheimer's disease.

Alzheimer's disease (AD) is marked by several cellular and molecular damage. Therefore, the therapeutic interest of multi-target molecules is increasingly justified. Polyphenols presenting multiple pharmacological effects would be more efficient. In this study, beneficial effects of trans ε-viniferin, a natural polyphenol were thus evaluated. This study reported that this stilbenoid (1) induced the disaggregation of amyloid ß (Aß) peptide and (2) rescued inflammation in murine primary neuronal cultures. These both effects are higher than those of resveratrol, and so, trans ε-viniferin could be a good therapeutic multi-target candidate.

There is no correlation between peripheral inflammation and cognitive status at diagnosis in Alzheimer's disease.

BACKGROUND: Besides the neurofibrillary tangles and amyloid plaques, an inflammatory process is involved at central and peripheral levels in Alzheimer's disease (AD). We aimed to determine whether peripheral inflammatory parameter levels, in plasma and in peripheral blood mononuclear cells (PBMCs), could be correlated with the cognitive status at the time of AD diagnosis. METHODS: Patients were included at diagnosis with MMSE score between 16 and 25 and were naive of symptomatic treatment for AD. C-reactive protein >10 mg/L and any acute or chronic inflammation were considered as exclusion criteria. Cognitive assessment also included the ADAScog scale. Plasma interleukins (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and the chemokine ligand 5 (CCL5) were measured using Luminex(®) X-MAP(®) technology. A subgroup of patients also underwent measures of these parameters in extracellular and intracellular compartments of PBMCs (ancillary study). RESULTS: One hundred and nine patients were included; mean age 79.4 ± 6.8 years with 37 patients in the ancillary study. The mean values of IL-1ß, TNF-α, IL-6 and CCL5 values were 1.49, 7.18, 3.09 and 69,615.81 pg/mL, respectively. No correlation between plasma cytokines or chemokine levels and cognitive scores was found. In PBMCs, the levels of cytokines were detectable but did not either show any correlation with cognitive scores. CONCLUSION: Our data indicate that at diagnosis, peripheral levels of cytokines and CCL5 display low values without any correlation with the cognitive status. Further results of our study will show if these circulating markers are related to the progression of AD.

Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice.

BACKGROUND: In recent years, studies have sought to understand the mechanisms involved in the alteration of autophagic flux in Alzheimer's disease (AD). Alongside the recent description of the impairment of lysosomal acidification, we wanted to study the relationships between inflammation and autophagy, two physiological components deregulated in AD. Therefore, a longitudinal study was performed in APPswePS1dE9 transgenic mice at three, six and twelve months of age. METHODS: Autophagic markers (Beclin-1, p62 and LC3) and the activation of mammalian Target of Rapamycin (mTOR) signaling pathway were quantified by western blot. Cytokine levels (IL-1ß, TNF-α and IL-6) were measured by ELISA. Transmission electron microscopy was performed to detect autophagic vacuoles. Mann-Whitney tests were used to compare wild-type (WT) versus APPswePS1dE9 mice. Longitudinal changes in parameters were analyzed with a Kruskal-Wallis test followed by a post-hoc Dunn's test. Correlation between two parameters was assessed using a Spearman test. RESULTS: Compared to 12-month old WT mice, 12-month old APPswePS1dE9 mice had higher levels of IL-1ß and TNF-α, a greater inhibition of the mTOR signaling pathway and lower levels of Beclin-1 expression both in cortex and hippocampus. Regarding the relationship of the various parameters in 12-month old APPswePS1dE9 mice, Beclin-1 rates were positively correlated with IL-1ß and TNF-α levels. And, on the contrary, TNF-α levels were inversely correlated with the levels of mTOR activation. Altogether, these results suggest that inflammation could induce autophagy in APPswePS1dE9 mice. However, these transgenic mice displayed a large accumulation of autophagic vesicles within dystrophic neurons in cortex and hippocampus, indicating a terminal failure in the autophagic process. CONCLUSIONS: This first demonstration of relationships between inflammation and autophagy in in vivo models of AD should be taken into account in new therapeutic strategies to prevent inflammation and/or stimulate autophagy in advanced neurodegenerative process such as AD.

Involvement of interleukin-1ß in the autophagic process of microglia: relevance to Alzheimer's disease.

BACKGROUND: Autophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer's Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined. METHODS: Here, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (Aß42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls' test. RESULTS: Aß42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1ß, TNF-α, and IL-6) or IL-1ß alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1ß in the induction of autophagy in tri-cultures in the presence or absence of Aß42. However, the vulnerability of the autophagic process in purified microglia to IL-1ß was prevented by Aß42. CONCLUSION: These findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1ß in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.

Identification of Intron Retention in the Slc16a3 Gene Transcript Encoding the Transporter MCT4 in the Brain of Aged and Alzheimer-Disease Model (APPswePS1dE9) Mice.

The monocarboxylate transporter 4 (MCT4; Slc16a3) is expressed in the central nervous system, notably by astrocytes. It is implicated in lactate release and the regulation of glycolytic flux. Whether its expression varies during normal and/or pathological aging is unclear. As the presence of its mature transcript in the brain of young and old mice was determined, an unexpectedly longer RT-PCR fragment was detected in the mouse frontal cortex and hippocampus at 12 vs. 3 months of age. Cultured astrocytes expressed the expected 516 base pair (bp) fragment but treatment with IL-1ß to mimic inflammation as can occur during aging led to the additional expression of a 928 bp fragment like that seen in aged mice. In contrast, cultured pericytes (a component of the blood-brain barrier) only exhibited the 516 bp fragment. Intriguingly, cultured endothelial cells constitutively expressed both fragments. When RT-PCR was performed on brain subregions of an Alzheimer mouse model (APPswePS1dE9), no fragment was detected at 3 months, while only the 928 bp fragment was present at 12 months. Sequencing of MCT4 RT-PCR products revealed the presence of a remaining intron between exon 2 and 3, giving rise to the longer fragment detected by RT-PCR. These results unravel the existence of intron retention for the MCT4 gene in the central nervous system. Such alternative splicing appears to increase with age in the brain and might be prominent in neurodegenerative diseases such as Alzheimer's disease. Hence, further studies in vitro and in vivo of intron 2 retention in the Slc16a3 gene transcript are required for adequate characterization concerning the biological roles of Slc16a3 isoforms in the context of aging and Alzheimer's disease pathology.

Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer's disease.

One of the pathological hallmarks of Alzheimer's disease (AD) is deposition of extracellular amyloid-beta (Abeta) peptide, which is generated from the cleavage of amyloid precursor protein (APP). Accumulation of Abeta is thought to associate with the progressive neuronal death observed in AD. However, the precise signaling mechanisms underlying the action of Abeta in AD pathophysiology are not completely understood. Here, we report the involvement of the transcription factor signal transducer and activator of transcription 3 (STAT3) in mediating Abeta-induced neuronal death. We find that tyrosine phosphorylation of STAT3 is elevated in the cortex and hippocampus of APP/PS1 transgenic mice. Treatment of cultured rat neurons with Abeta or intrahippocampal injection of mice with Abeta both induces tyrosine phosphorylation of STAT3 in neurons. Importantly, reduction of either the expression or activation of STAT3 markedly attenuates Abeta-induced neuronal apoptosis, suggesting that STAT3 activation contributes to neuronal death after Abeta exposure. We further identify Tyk2 as the tyrosine kinase that acts upstream of STAT3, as Abeta-induced activation of STAT3 and caspase-3-dependent neuronal death can be inhibited in tyk2(-/-) neurons. Finally, increased tyrosine phosphorylation of STAT3 is also observed in postmortem brains of AD patients. Our observations collectively reveal a novel role of STAT3 in Abeta-induced neuronal death and suggest the potential involvement of Tyk2/STAT3 signaling in AD pathophysiology.

Interaction of double-stranded RNA-dependent protein kinase (PKR) with the death receptor signaling pathway in amyloid beta (Abeta)-treated cells and in APPSLPS1 knock-in mice.

For 10 years, research has focused on signaling pathways controlling translation to explain neuronal death in Alzheimer Disease (AD). Previous studies demonstrated in different cellular and animal models and AD patients that translation is down-regulated by the activation of double-stranded RNA-dependent protein kinase (PKR). Among downstream factors of PKR, the Fas-associated protein with a death domain (FADD) and subsequent activated caspase-8 are responsible for PKR-induced apoptosis in recombinant virus-infected cells. However, no studies have reported the role of PKR in death receptor signaling in AD. The aim of this project is to determine physical and functional interactions of PKR with FADD in amyloid-beta peptide (Abeta) neurotoxicity and in APP(SL)PS1 KI transgenic mice. In SH-SY5Y cells, results showed that Abeta42 induced a large increase in phosphorylated PKR and FADD levels and a physical interaction between PKR and FADD in the nucleus, also observed in the cortex of APP(SL)PS1 KI mice. However, PKR gene silencing or treatment with a specific PKR inhibitor significantly prevented the increase in pT(451)-PKR and pS(194)-FADD levels in SH-SY5Y nuclei and completely inhibited activities of caspase-3 and -8. The contribution of PKR in neurodegeneration through the death receptor signaling pathway may support the development of therapeutics targeting PKR to limit neuronal death in AD.

Trans ε-Viniferin Decreases Amyloid Deposits With Greater Efficiency Than Resveratrol in an Alzheimer's Mouse Model.

In a previous study, we showed that viniferin decreased amyloid deposits and reduced neuroinflammation in APPswePS1dE9 transgenic mice between 3 and 6 months of age. In the present study, wild type and APPswePS1dE9 transgenic mice were treated from 7 to 11 or from 3 to 12 months by a weekly intraperitoneal injection of either 20 mg/kg viniferin or resveratrol or their vehicle, the polyethylene glycol 200 (PEG 200). The cognitive status of the mice was evaluated by the Morris water maze test. Then, amyloid burden and neuroinflammation were quantified by western-blot, Enzyme-Linked ImmunoSorbent Assay (ELISA), immunofluorescence, and in vivo micro-Positon Emission Tomography (PET) imaging. Viniferin decreased hippocampal amyloid load and deposits with greater efficiency than resveratrol, and both treatments partially prevented the cognitive decline. Furthermore, a significant decrease in brain uptake of the TSPO PET tracer [18F]DPA-714 was observed with viniferin compared to resveratrol. Expression of GFAP, IBA1, and IL-1ß were decreased by viniferin but PEG 200, which was very recently shown to be a neuroinflammatory inducer, masked the neuroprotective power of viniferin.

EphrinA5 protein distribution in the developing mouse brain.

BACKGROUND: EphrinA5 is one of the best-studied members of the Eph-ephrin family of guidance molecules, known to be involved in brain developmental processes. Using in situ hybridization, ephrinA5 mRNA expression has been detected in the retinotectal, the thalamocortical, and the olfactory systems; however, no study focused on the distribution of the protein. Considering that this membrane-anchored molecule may act far from the neuron soma expressing the transcript, it is of a crucial interest to localize ephrinA5 protein to better understand its function. RESULTS: Using immunohistochemistry, we found that ephrinA5 protein is highly expressed in the developing mouse brain from E12.5 to E16.5. The olfactory bulb, the cortex, the striatum, the thalamus, and the colliculi showed high intensity of labelling, suggesting its implication in topographic mapping of olfactory, retinocollicular, thalamocortical, corticothalamic and mesostriatal systems. In the olfactory nerve, we found an early ephrinA5 protein expression at E12.5 suggesting its implication in the guidance of primary olfactory neurons into the olfactory bulb. In the thalamus, we detected a dynamic graduated protein expression, suggesting its role in the corticothalamic patterning, whereas ephrinA5 protein expression in the target region of mesencephalic dopaminergic neurones indicated its involvement in the mesostriatal topographic mapping. Following E16.5, the signal faded gradually and was barely detectable at P0, suggesting a main role for ephrinA5 in primary molecular events in topographic map formation. CONCLUSION: Our work shows that ephrinA5 protein is expressed in restrictive regions of the developing mouse brain. This expression pattern points out the potential sites of action of this molecule in the olfactory, retinotectal, thalamocortical, corticothalamic and mesostriatal systems, during development. This study is essential to better understand the role of ephrinA5 during developmental topographic mapping of connections and to further characterise the mechanisms involved in pathway restoration following cell transplantation in the damaged brain.

Natural stilbenes effects in animal models of Alzheimer's disease.

Alzheimer's disease is one of the most frequent neurodegenerative diseases. This pathology is characterized by protein aggregates, mainly constituted by amyloid peptide and tau, leading to neuronal death and cognitive impairments. Drugs currently proposed to treat this pathology do not prevent neurodegenerative processes and are mainly symptomatic therapies. However, stilbenes presenting multiple pharmacological effects could be good potential therapeutic candidates. The aim of this review is to gather the more significant papers among the broad literature on this topic, concerning the beneficial effects of stilbenes (resveratrol derivatives) in animal models of Alzheimer's disease. Indeed, numerous studies focus on cellular models, but an in vivo approach remains of primary importance since in animals (mice or rats, generally), bioavailability and metabolism are taken into account, which is not the case in in vitro studies. Furthermore, examination of memory ability is feasible in animal models, which strengthens the relevance of a compound with a view to future therapy in humans. This paper is addressed to any researcher who needs to study untested natural stilbenes or who wants to experiment the most effective natural stilbenes in largest animals or in humans. This review shows that resveratrol, the reference polyphenol, is largely studied and seems to have interesting properties on amyloid plaques, and cognitive impairment. However, some resveratrol derivatives such as gnetin C, trans-piceid, or astringin have never been tested on animals. Furthermore, pterostilbene is of particular interest, by its improvement of cognitive disorders and its neuroprotective role. It could be relevant to evaluate this molecule in clinical trials.

PKR, a cognitive decline biomarker, can regulate translation via two consecutive molecular targets p53 and Redd1 in lymphocytes of AD patients.

In Alzheimer's disease (AD), the control of translation is dysregulated, precisely, two opposite pathways: double-stranded RNA-dependent protein kinase (PKR) is up-regulated and mammalian target of rapamycin (mTOR) is down-regulated. These biochemical alterations were found at the periphery in lymphocytes of AD patients and were significantly correlated with cognitive and memory test scores. However, the molecular crosslink between these two opposite signalling pathways remains unknown. The tumour suppressor p53 and Redd1 (regulated in development and DNA damage response) could be two downstream targets of active PKR to explain the breakdown of translation in AD patients. In this study, the protein and gene levels of p53 and Redd1 were assayed in lymphocytes of AD patients and in age-matched controls by Western blotting and RT-PCR. Furthermore, correlations were analysed with both the level of active PKR and the Mini Mental State Examination score (MMSE). The results show that the gene and protein levels of p53 and Redd1 were significantly increased about 1.5-fold for both gene and Redd1 protein and 2.3-fold for active p53 in AD lymphocytes compared to age-matched controls. Furthermore, statistical correlations between proteins and genes suggest that active PKR could phosphorylate p53 which could induce the transcription of Redd1 gene. No correlations were found between MMSE scores and levels of p53 or Redd1, contrary to active PKR levels. PKR represents a cognitive decline biomarker able to dysregulate translation via two consecutive targets p53 and Redd1 in AD lymphocytes.

PKR, the double stranded RNA-dependent protein kinase as a critical target in Alzheimer's disease.

Amyloid beta-peptide (Abeta) deposits and neurofibrillary tangles are key hallmarks in Alzheimer's disease (AD). Abeta stimulates many signal transducers involved in the neuronal death. However, many mechanisms remain to be elucidated because no definitive therapy of AD exists. Some studies have focused on the control of translation which involves eIF2 and eIF4E, main eukaryotic factors of initiation. The availability of these factors depends on the activation of the double-stranded RNA-dependent protein kinase (PKR) and the mammalian target of rapamycin (mTOR), respectively. mTOR positively regulates the translation while PKR results in a protein synthesis shutdown. Many studies demonstrated that the PKR signalling pathway is up-regulated in cellular and animal models of AD and in the brain of AD patients. Interestingly, our results showed that phosphorylated PKR and eIF2alpha levels were significantly increased in lymphocytes of AD patients. These modifications were significantly correlated with cognitive and memory test scores performed in AD patients. On the contrary, the mTOR signalling pathway is down-regulated in cellular and animal models of AD. Recently, we showed that p53, regulated protein in development and DNA damage response 1 and tuberous sclerosis complex 2 could represent molecular links between PKR and mTOR signalling pathways. PKR could be an early biomarker of the neuronal death and a critical target for a therapeutic programme in AD.

Evidence of molecular links between PKR and mTOR signalling pathways in Abeta neurotoxicity: role of p53, Redd1 and TSC2.

The control of translation is disturbed in Alzheimer's disease (AD). This study analysed the crosslink between the up regulation of double-stranded RNA-dependent-protein kinase (PKR) and the down regulation of mammalian target of rapamycin (mTOR) signalling pathways via p53, the protein Regulated in the Development and DNA damage response 1 (Redd1) and the tuberous sclerosis complex (TSC2) factors in two beta-amyloid peptide (Abeta) neurotoxicity models. In SH-SY5Y cells, Abeta42 induced an increase of P(T451)-PKR and of the ratio p66/(p66+p53) in nuclei and a physical interaction between these proteins. Redd1 gene levels increased and P(T1462)-TSC2 decreased. These disturbances were earlier in rat primary neurons with nuclear co-localization of Redd1 and PKR. The PKR gene silencing in SH-SY5Y cells prevented these alterations. p53, Redd1 and TSC2 could represent the molecular links between PKR and mTOR in Abeta neurotoxicity. PKR could be a critical target in a therapeutic program of AD.

Trans ε viniferin decreases amyloid deposits and inflammation in a mouse transgenic Alzheimer model.

As Alzheimer's disease (AD) induces several cellular and molecular damages, it could be interesting to use multi-target molecules for therapeutics. We previously published that trans ε-viniferin induced the disaggregation of Aß42 peptide and inhibited the inflammatory response in primary cellular model of AD. Here, effects of this stilbenoid were evaluated in transgenic APPswePS1dE9 mice. We report that trans ε-viniferin could go through the blood brain barrier, reduces size and density of amyloid deposits and decreases reactivity of astrocytes and microglia, after a weekly intraperitoneal injection at 10 mg/kg from 3 to 6 months of age.

Relevance of electroencephalogram assessment in amyloid and tau pathology in rat.

In order to contribute to a better knowledge on the relationship between amyloid and tau pathology, and electroencephalography (EEG) disturbances, the aim of this study was to evaluate the effects of injection of beta amyloid Abeta(1-42) peptide, tau (a recombinant AAV (Adeno-Associated Virus) containing the human transgene tau with the P301 L mutation on rats and the combination of both, on the power of brain's rhythm (delta, theta, alpha, beta and gamma waves) during the different sleep/wake states of animals by EEG recording. Currently, no preclinical studies explore the effect of the tau pathology on EEG. The experimentations were performed 3 weeks and 3 months post injections. Beta amyloid deposits and hyperphosphorylated Tau are observed by immunohistofluorescence, only in the hippocampus. Furthermore, using a radial arm water maze, the main effect was observed on working memory which was significantly impaired in Abeta-Tau group only 3 months post injections. However, on EEG, as early as the 3rd week, an overall decrease of the EEG bands power was observed in the treated groups, particularly the theta waves during the rapid eye movement (REM) sleep. Beta amyloid was mainly involved in these perturbations. Obviously, EEG seems to be an interesting tool in the early diagnostic of amyloid and tau pathologies, with a good sensitivity and the possibility to perform a follow up during a large period.