Tau protein kinases: involvement in Alzheimer's disease.

Neuroinflammation is thought to be important in Alzheimer's disease pathogenesis. Mast cells are a key component of the inflammatory network and participate in the regulation of the blood-brain barrier's permeability. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. As the brain is rich in mast cells, the therapeutic potential of masitinib as an adjunct therapy to standard care was investigated. A randomised, placebo-controlled, phase 2 study was performed in patients with mild-to-moderate Alzheimer's disease, receiving masitinib as an adjunct to cholinesterase inhibitor and/or memantine. Patients were randomly assigned to receive masitinib (n = 26) (starting dose of 3 or 6 mg/kg/day) or placebo (n = 8), administered twice daily for 24 weeks. The primary endpoint was change from baseline in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-Cog) to assess cognitive function and the related patient response rate. The rate of clinically relevant cognitive decline according to the ADAS-Cog response (increase >4 points) after 12 and 24 weeks was significantly lower with masitinib adjunctive treatment compared with placebo (6% vs. 50% for both time points; P = 0.040 and P = 0.046, respectively). Moreover, whilst the placebo treatment arm showed worsening mean ADAS-Cog, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, and Mini-Mental State Examination scores, the masitinib treatment arm reported improvements, with statistical significance between treatment arms at week 12 and/or week 24 (respectively, P = 0.016 and 0.030; P = 0.035 and 0.128; and P = 0.047 and 0.031). The mean treatment effect according to change in ADAS-Cog score relative to baseline at weeks 12 and 24 was 6.8 and 7.6, respectively. Adverse events occurred more frequently with masitinib treatment (65% vs. 38% of patients); however, the majority of events were of mild or moderate intensity and transitory. Severe adverse events occurred at a similar frequency in the masitinib and placebo arms (15% vs. 13% of patients, respectively). Masitinib-associated events included gastrointestinal disorders, oedema, and rash. Masitinib administered as add-on therapy to standard care during 24 weeks was associated with slower cognitive decline in Alzheimer's disease, with an acceptable tolerance profile. Masitinib may therefore represent an innovative avenue of treatment in Alzheimer's disease. This trial provides evidence that may support a larger placebo-controlled investigation. Clinicaltrials.gov NCT00976118

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Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial

Structural networks in Alzheimer's disease.

Cognitive and behavioral acts go along with highly coordinated spatiotemporal activity patterns in neuronal networks. Most of these patterns are synchronized by coherent membrane potential oscillations within and between local networks. By entraining multiple neurons into a common time regime, such network oscillations form a critical interface between cellular activity and large-scale systemic functions. Synaptic integrity is altered in neurodegenerative diseases, and it is likely that this goes along with characteristic changes of coordinated network activity. This notion is supported by EEG recordings from human patients and from different animal models of such disorders. However, our knowledge about the pathophysiology of network oscillations in neurodegenerative diseases is surprisingly incomplete, and increased research efforts are urgently needed. One complicating factor is the pronounced diversity of network oscillations between different brain regions and functional states. Pathological changes must, therefore, be analyzed separately in each condition and affected area. However, cumulative evidence from different diseases may result, in the future, in more unifying “oscillopathy” concepts of neurodegenerative diseases. In this review, we report present evidence for pathological changes of network oscillations in Alzheimer’s disease (AD), one of the most prominent and challenging neurodegenerative disorders. The heterogeneous findings from AD are contrasted to Parkinson’s disease, where motor-related changes in specific frequency bands do already fulfill criteria of a valid biomarker.

Neuronal Network Oscillations in Neurodegenerative Diseases

Alzheimer's disease (AD) is a devastating neurodegenerative dementing illness. Early diagnosis at the prodromal stage is an important topic of current research. Significant advances were recently made in the validation process of several biomarkers, including structural/amyloid imaging, cerebrospinal fluid measurements, and glucose positron emission tomography. Nevertheless, there remains a need to develop an efficient, low cost, potentially portable, noninvasive biomarker in the diagnosis, course, or treatment of AD. There is also a great need for a biomarker that would reflect functional brain dynamic changes within a very short time period, such as milliseconds, to provide information about cognitive deficits. Electrophysiological methods have the highest time resolution for reflecting brain dynamics in cognitive impairments. There are several strategies available for measuring cognitive changes, including spontaneous electroencephalography (EEG), sensory-evoked oscillations (SEOs), and event-related oscillations (EROs). The term "sensory-evoked" (SE) implies responses elicited upon simple sensory stimulation, whereas "event-related" (ER) indicates responses elicited upon a cognitive task, generally an oddball paradigm. Further selective connectivity deficit in sensory or cognitive networks is reflected by coherence measurements. When simple sensory stimulus is used, a sensory network becomes activated, whereas an oddball task initiates an activation in a sensory network and additionally in a related cognitive network. In AD, spontaneous activity reveals a topographically changed pattern of oscillations. In addition, the most common finding in spontaneous EEG of AD is decrease of fast and increase of slow frequencies. The hyperexcitability of motor and sensory cortices in AD has been demonstrated in many studies. The motor cortex hyperexcitability has been shown by transcranial magnetic stimulation studies. Also, the SEOs reflecting sensory network indicate a visual sensory cortex hyperexcitability in AD, as demonstrated by increased responses over posterior regions of the hemispheres. On the other hand, ERO studies reflecting activation of a cognitive network imply decreased responses in fronto-central regions of the brain in delta and theta frequencies. Coherence studies show the connectivity between different parts of the brain. Studies of SE coherence in mild AD subjects imply almost intact connectivity in all frequency ranges, whereas ER coherence is decreased in wide connections in alpha, theta, and delta frequency ranges. Moreover, alpha ER coherence seems to be sensitive to cholinergic treatment in AD. In further research in a search of AD biomarkers, multimodal methods should be introduced to electrophysiology in order to validate these methods. Standardization and harmonization of user-friendly acquisition and analysis protocols in larger cohort populations are also needed in order to incorporate electrophysiology as a part of the clinical criteria of AD.

Biomarkers in Alzheimer's disease with a special emphasis on event-related oscillatory responses.

Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of beta-amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to betaAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of betaAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to betaAP(25-35) on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that betaAP(25-35), reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence betaAP(35-25) and is reproduced by the full-length peptide betaAP(1-42). Correspondingly betaAP(25-35), but not the inverse sequence betaAP(35-25), reduces theta-like activity recorded from the hippocampus in vivo. The betaAP(25-35)-induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn-kinase on the betaAP(25-35)-induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn-knockout mice. In conclusion, our data suggest that betaAP acutely affects proper hippocampal function through a Fyn-dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease.

Beta-amyloid protein (25-35) disrupts hippocampal network activity: role of Fyn-kinase.

Beta-like hippocampal network activity is differentially affected by amyloid beta peptides.

Soluble amyloid β (Aβ) oligomers might trigger early cognitive deficit in Alzheimers Disease (AD) through the impairment of proper neuronal network function. We have recently shown that the short sequence Aβ25-35 affects the spontaneous activity in hippocampal slices, when was added to the bath, at high nanomolar concentrations. In the present study, we aimed to characterize the effects of the oligomerized full length sequence Aβ1-42 on the spontaneous network activity in the CA1 hippocampal area testing whether such effects are age dependent. By performing extracellular field recordings of spontaneous network activity of hippocampal slices, we found that an oligomerized solution of Aβ1-42 (osAβ) potently inhibit, in a dose-dependent manner, the spontaneous hippocampal network activity with an IC50 of 0.4 ± 3.2 nM and a maximal effect reached around 10 nM. While spontaneous hippocampal network activity is unaffected by age, the sensitivity of spontaneous hippocampal network activity to osAβ (10 nM) appears to be increased in slices from older animals. Moreover, to see a significant reduction in spontaneous network activity in slices from animals in their second week of life 100nM osAβ was needed. The osAβ-induced reduction in hippocampal network activity is accompanied by a presynaptic reduction in both spontaneous and miniature synaptic potentials. Finally, we demonstrated that the effect produced by osAβ on spontaneous network activity was specific, reversible and unrelated with cell death. In conclusion, our data show that osAβ alters hippocampal network activity at concentrations commonly observed in AD patients and that such effect of osAβ increases with age.

Abraham Márquez-Ramos

Papers

Beta-amyloid protein (25-35) disrupts hippocampal network activity: role of Fyn-kinase.

Beta-like hippocampal network activity is differentially affected by amyloid beta peptides.

Amyloid β oligomers decrease hippocampal spontaneous network activity in an age-dependent manner.