Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons

Cell cycle reentry followed by neuronal hyperploidy and synaptic failure are two early hallmarks of Alzheimer’s disease (AD), however their functional connection remains unexplored. To address this question, we induced cell cycle reentry in cultured cortical neurons by expressing SV40 large T antigen. Cell cycle reentry was followed by hyperploidy in ~70% of cortical neurons, and led to progressive axon initial segment loss and reduced density of dendritic PSD-95 puncta, which correlated with diminished spike generation and reduced spontaneous synaptic activity. This manipulation also resulted in delayed cell death, as previously observed in AD-affected hyperploid neurons. Membrane depolarization by high extracellular potassium maintained PSD-95 puncta density and partially rescued both spontaneous synaptic activity and cell death, while spike generation remained blocked. This suggests that AD-associated hyperploid neurons can be sustained in vivo if integrated in active neuronal circuits whilst promoting synaptic dysfunction. Thus, cell cycle reentry might contribute to cognitive impairment in early stages of AD and neuronal death susceptibility at late stages.This work was supported by Ministerio de Economía y Competitividad Grants SAF2015-68488-R (J.M.F.) and BFU2013-47265-R and BFU2016-75107-P (G.P.), and Intramural Grant 201620I017 (G.P.).Peer reviewe

A Guide to Senolytic Intervention in Neurodegenerative Disease

Cellular senescence is a potential tumor-suppressive mechanism that generally results in an irreversible cell cycle arrest. Senescent cells accumulate with age and actively secrete soluble factors, collectively termed the ‘senescence-associated secretory phenotype’ (SASP), which has both beneficial and detrimental effects. Although the contribution of senescent cells to age-related pathologies has been well-established outside the brain, emerging evidence indicates that brain cells also undergo cellular senescence and contribute to neuronal loss in the context of age-related neurodegenerative diseases. Contribution of senescent cells in the pathogenesis of neurological disorders has led to the possibility of eliminating senescence cells via pharmacological compounds called senolytics. Recently several senolytics have been demonstrated to elicit improved cognitive performance and healthspan in mouse models of neurodegeneration. However, their translation for use in the clinic still holds several potential challenges. This review summarizes available senolytics, their purported mode of action, and possible off-target effects. We also discuss possible alternative strategies that may help minimize potential side-effects associated with the senolytics approach

Primary neurons can enter M-phase

Differentiated neurons can undergo cell cycle re-entry during pathological conditions, but it remains largely accepted that M-phase is prohibited in these cells. Here we show that primary neurons at post-synaptogenesis stages of development can enter M-phase. We induced cell cycle re-entry by overexpressing a truncated Cyclin E isoform fused to Cdk2. Cyclin E/Cdk2 expression elicits canonical cell cycle checkpoints, which arrest cell cycle progression and trigger apoptosis. As in mitotic cells, checkpoint abrogation enables cell cycle progression through S and G2-phases into M-phase. Although most neurons enter M-phase, only a small subset undergo cell division. Alternatively, neurons can exit M-phase without cell division and recover the axon initial segment, a structural determinant of neuronal viability. We conclude that neurons and mitotic cells share S, G2 and M-phase regulation.This study was supported by Ministerio de Economía y Competitividad grant SAF2015-68488-R (J.M.F.), SAF2015-65315-R (J.J.G.), and Ministerio de Educación, Cultura y Deporte grant FPU1305084 (C.C.W.).Peer reviewe

Physics of corrosion-resistant Mg/SiC multilayer coatings for EUV sources

Invited paper; Prague, Czech Republic, 13–16 April 2015The 25-80 nm wavelength region is part of the operational range of extreme ultraviolet (EUV) synchrotron, free-electron laser and tabletop laser sources, which often require multilayer-coated reflective optics. Mg/ SiC possesses a unique combination of favorable reflective properties in the 25-80 nm wavelength range: high reflectance, near-zero film stress, good spectral selectivity and thermal stability up to 350? C. However, Mg/SiC suffers from Mg-related atmospheric corrosion, an insidious and unpredictable problem which completely degrades reflectance and has prevented Mg/SiC from being used in scientific experiments and applications that require long lifetime stability. In recent work, we elucidated the origins and mechanisms of corrosion propagation within Mg/SiC multilayers and demonstrated efficient and simple-to-implement Al-Mg corrosion barriers for Mg/SiC multilayers. We also demonstrated Mg/SiC multilayers with corrosion barriers which achieve high reflectance in up to three narrow bands simultaneously. In this presentation, we focus on the physics of spontaneous intermixing and amorphization of the Al and Mg layers inside the Al-Mg corrosion barriers. We also discuss the long-term reflective properties of a variety of Mg/SiC multilayer concepts, with and without corrosion barriers. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract No. DE-AC52-07NA27344.Peer Reviewe