Georges Mairet-Coello

The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation

Amyloid-β 1-42 (Aβ42) oligomers are synaptotoxic for excitatory cortical and hippocampal neurons and might play a role in early stages of Alzheimers disease (AD) progression. Recent results suggested that Aβ42 oligomers trigger activation of AMP-activated kinase (AMPK), and its activation is increased in the brain of patients with AD. We show that increased intracellular calcium [Ca²⁺](i) induced by NMDA receptor activation or membrane depolarization activates AMPK in a CAMKK2-dependent manner. CAMKK2 or AMPK overactivation is sufficient to induce dendritic spine loss. Conversely, inhibiting their activity protects hippocampal neurons against synaptotoxic effects of Aβ42 oligomers in vitro and against the loss of dendritic spines observed in the human APP(SWE,IND)-expressing transgenic mouse model in vivo. AMPK phosphorylates Tau on KxGS motif S262, and expression of Tau S262A inhibits the synaptotoxic effects of Aβ42 oligomers. Our results identify a CAMKK2-AMPK-Tau pathway as a critical mediator of the synaptotoxic effects of Aβ42 oligomers.

T807, a reported selective tau tracer, binds with nanomolar affinity to monoamine oxidase a

to determine the legal implications of biomarkers for insurance or employment purposes. Federal law prohibiting employment discrimination based on disability offered potential protections for individuals. Comparatively, federal law explicitly delegates insurance regulation to states. Regulations vary between states on issues regarding underwriting, eligibility, and benefits. Additionally, while the Affordable Care Act provides protections regarding health insurance by prohibiting discrimination based on pre-existing conditions, similar protections are not extended for life, disability, or long-term care insurance. Conclusions: Current laws are largely insufficient to protect individuals from employment or insurance discrimination based on preclinical Alzheimer’s disease status. This supports exploring the potential routes for advocacy to improve protections and research regarding other routes for mitigating the potential risks related to insurance and employment. This work was supported by a grant from the Alzheimer’s Association (MNIRGD-14-319284).

The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases: AV-1451 Tau Pet Tracer Binds Mao-a and -B

Background: Lilly/Avids AV‐1451 is one of the most advanced tau PET tracers in the clinic. Although results obtained in Alzheimers disease patients are compelling, discrimination of tracer uptake in healthy individuals and patients with supranuclear palsy (PSP) is less clear as there is substantial overlap of signal in multiple brain regions. Moreover, accurate quantification of [18F]AV‐1451 uptake in Alzheimers disease may not be possible.

Involvement of 'stress-response' kinase pathways in Alzheimer's disease progression.

Alzheimers disease (AD) is the most prevalent cause of dementia, affecting more than 25 million people worldwide. Current models of the pathophysiological mechanisms of AD suggest that the accumulation of soluble oligomeric forms of amyloid-β (Aβ) peptides causes early loss of excitatory synapses and impairs synaptic plasticity. The signaling pathways mediating Aβ oligomer-induced impairment of synaptic plasticity and loss of excitatory synapses are only beginning to be unraveled. Here, we review recent evidence supporting the critical contribution of conserved stress-response kinase pathways in AD progression.

PREVENTION OF TAU SEEDING AND SPREADING IN TRANSGENIC MOUSE MODELS BASED ON INTRACRANIAL-INJECTION OF P301L-K18 FIBRILS OR ALZHEIMER’S DISEASE LYSATE BY PASSIVE IMMUNOTHERAPY

and potently inhibitedDYRK1a kinase activity (IC501⁄4 2nM). In cells, SM07883 reduced pTau at the Threonine 212 site (EC501⁄4 16nM). In pharmacokinetic studies, SM07883 demonstrated good exposure across multiple species (mouse brain : plasma ratio > 3). Compared to vehicle,WTmice showed a dose dependent reduction of transiently induced brain pTau in a pharmacodynamic model starting with a single, 1.25mg/kg SM07883 dose (47%, p1⁄40.0002). JNPL3mice treated with SM07883 demonstrated significant (p<0.05) reductions in Tau hyperphosphorylation, oligomeric and aggregated Tau, and significantly lowerNFTstainingcompared tovehicle.ReducedGFAPimmunoreactivity was confirmed by Western Blotting (37%, p1⁄40.0010). SM07883 was well tolerated with weight gain over the 3 month treatment period and reduced morbidity and mortality in treated animals compared to vehicle. Motor function in the wire hanging test was significantly improved in SM07883-treated JNPL3 mice compared to vehicle (p1⁄40.034) starting 5 weeks after treatment initiation. Conclusions: SM07883, a selective and potent, oral, brain-penetrant, DYRK1a inhibitor significantly reduced Tau phosphorylation, the effects of pathological Tau overexpression, and neuroinflammation, and improved functional endpoints compared to vehicle. SM07883 has potential as a treatment for chronic tauopathies such as AD.

Epitope determines efficacy of therapeutic anti-Tau antibodies in a functional assay with human Alzheimer Tau

In Alzheimer’s disease (AD) and other tauopathies, the cytosolic protein Tau misfolds and forms intracellular aggregates which accumulate within the brain leading to neurodegeneration. Clinical progression is tightly linked to the progressive spread of Tau pathology throughout the brain, and several lines of evidence suggest that Tau aggregates or “seeds” may propagate pathology by spreading from cell to cell in a “prion like” manner. Accordingly, blocking the spread of extracellular seeds with an antibody could be a viable therapeutic approach. However, as the structure of Tau seeds is unknown, it is only possible to rationally design therapeutic Tau antibodies by making a priori assumptions. To avoid this, we developed a robust and quantitative cell based assay and employed an unbiased screening approach to identify the antibody with the highest activity against human Tau seeds. The selected antibody (D), directed to the mid-region of Tau (amino acids 235–250), potently blocked the seeding of human AD Tau and was also fully efficacious against seeds from progressive supranuclear palsy. When we compared this antibody with previously described reference antibodies, we were surprised to find that none of these antibodies showed comparable efficacy against human pathological seeds. Our data highlight the difficulty of predicting antibody accessible epitopes on pathological Tau seeds and question the potential efficacy of some of the Tau antibodies that are currently in clinical development.