Biology subjects

Buee, L.

Publications and source records attributed to Buee, L..

3 recordsLinked to original sources

bioRxiv2018

AMP-activated protein kinase is essential for the maintenance of energy levels during synaptic activation

While accounting for 2% of the total body mass, the brain is the organ that consumes the most energy. Although it is widely acknowledged that neuronal energy metabolism is tightly regulated, the mechanism how neurons meet their energy demand to sustain synaptic transmission remains poorly studied. Here we provide substantial evidence that the AMP-activated protein kinase (AMPK) plays a leading role in this process. Our results show that following synaptic activation, AMPK activation is required to sustain neuronal energy levels particularly through mitochondrial respiration. Further, our studies revealed that this metabolic plasticity regulated by AMPK is required for the expression of immediate early genes, synaptic plasticity and memory formation. These findings are important in the context of neurodegenerative disorders, as AMPK deregulation as it is observed in Alzheimers disease, impairs the metabolic response to synaptic activation. Altogether, our data provides the proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolism plasticity induced in response to synaptic activation.

neuroscience↗

bioRxiv2018

Contribution of the endosomal-lysosomal and proteasomal systems in Amyloid-β Precursor Protein derived fragments processing

A{beta} peptides, the major components of amyloid deposits of Alzheimers disease, are released following sequential cleavages by secretases of its precursor named the amyloid precursor protein (APP). In addition to secretases, degradation pathways, in particular the endosomal/lysosomal and proteasomal systems have also been reported to contribute to APP processing. However, the respective role of each of these pathways towards APP metabolism remains to be established. To address this, we used HEK 293 cells and primary neurons expressing full-length APPWT or the {beta}-secretase-derived C99 fragments ({beta}-CTFs) in which degradation pathways were selectively blocked using pharmacological drugs. APP metabolites, including carboxy-terminal fragments (CTFs), soluble APP (sAPP) and A{beta} peptides were studied. In this report, we show that APP-CTFs produced from endogenous or overexpressed full-length APP are mainly processed by {gamma}-secretase and the endosomal/lysosomal pathway, while in sharp contrast, overexpressed C99 alone is mainly degraded by the proteasome and to a lesser extent by {gamma}-secretase.

neuroscience↗

bioRxiv2017

Genome-wide Association Study Links APOEϵ4 and BACE1 Variants with Plasma Amyloid β Levels

INTRODUCTIONThere is increasing interest in plasma A{beta} as an endophenotype and biomarker of Alzheimers disease (AD). Identifying the genetic determinants of plasma A{beta} levels may elucidate important processes that determine plasma A{beta} measures. METHODSWe included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and plasma A{beta}1-40, A{beta}1-42 levels and A{beta}1-42/A{beta}1-40 ratio were used to perform genome-wide association studies, gene-based and pathway analyses. Significant variants and genes were followed-up for the association with PET A{beta} deposition and AD risk. RESULTSSingle-variant analysis identified associations across APOE for A{beta}1-42 and A{beta}1-42/A{beta}1-40 ratio, and BACE1 for A{beta}1-40. Gene-based analysis of A{beta}1-40 additionally identified associations for APP, PSEN2, CCK and ZNF397. There was suggestive interaction between a BACE1 variant and APOE{varepsilon}4 on brain A{beta} deposition. DISCUSSIONIdentification of variants near/in known major A{beta}-processing genes strengthens the relevance of plasma-A{beta} levels both as an endophenotype and a biomarker of AD.

genetics↗