ABSTRACT
Neuronal network dysfunction and cognitive decline constitute the most prominent features of Alzheimer's disease (AD), although mechanisms causing such impairments are yet to be determined. Here we report that virus-mediated delivery of the active spliced transcription factor X-Box binding protein 1s (XBP1s) in the hippocampus rescued spine density, synaptic plasticity and memory function in a mouse model of AD. XBP1s transcriptionally activated Kalirin-7 (Kal7), a protein that controls synaptic plasticity. In addition, we found reduced levels of Kal7 in primary neurons exposed to Aß oligomers, transgenic mouse models and human AD brains. Short hairpin RNA-mediated knockdown of Kal7 altered synaptic plasticity and memory formation in naive mice. Further, reduction of endogenous Kal7 compromised the beneficial effects of XBP1s in Alzheimer's model. Hence, our findings reveal that XBP1s is neuroprotective through a mechanism that engages Kal7 pathway with therapeutic implications in AD pathology.
Subject(s)
Alzheimer Disease/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Protein Serine-Threonine Kinases/metabolism , X-Box Binding Protein 1/metabolism , Adult , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Animals , CHO Cells , Cricetulus , Disease Models, Animal , Excitatory Postsynaptic Potentials/drug effects , Female , Guanine Nucleotide Exchange Factors/genetics , Hippocampus/metabolism , Humans , Male , Mice , Mice, Knockout , Middle Aged , Neuronal Plasticity , Neurons/metabolism , Primary Cell Culture , Transcription Factors/metabolism , X-Box Binding Protein 1/genetics , Young AdultABSTRACT
The γ-secretase is a multiprotein complex responsible for the ultimate cut yielding amyloid-ß peptides and their N-terminal truncated species. This complex is composed of at least four distinct entities, namely presenilin-1 (PS1) or PS2, anterior pharynx defective-1, presenilin enhancer-2 (Pen-2) and nicastrin. Very few studies examined the transcriptional regulation of this complex, and more precisely, whether some of the members functionally interact. Here, we summarize our previous data documenting the fact that Pen-2 controls cell death in a p53-dependent manner and our recent demonstration of a pivotal role of p53 as a regulator of Pen-2 transcription. As PS trigger amyloid precursor protein intracellular domain-dependent regulation of p53, our studies delineate a feedback control mechanism by which PS and Pen-2 functionally interact in a p53-dependent manner.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Gene Expression Regulation/physiology , Membrane Proteins/metabolism , Presenilins/metabolism , Tumor Suppressor Protein p53/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Humans , Multiprotein Complexes/metabolism , RNA, Messenger/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
We recently demonstrated that the presenilin-dependent gamma-secretase complex regulates the expression and activity of neprilysin, one of the main enzymes that degrade the amyloid beta-peptide (Abeta) which accumulates in Alzheimer's disease. Here, we examined the influence of endogenous nicastrin (NCT), a member of the gamma-secretase complex, on neprilysin physiology. We show that nicastrin deficiency drastically lowers neprilysin expression, membrane-bound activity and mRNA levels, but it did not modulate the expression of two other putative Abeta-cleaving enzymes, endothelin-converting enzyme and insulin-degrading enzyme. Furthermore, we show that nicastrin restores neprilysin activity and expression in nicastrin-deficient, but not presenilin-deficient fibroblasts, indicating that the control of neprilysin necessitates the complete gamma-secretase complex harbouring its four reported components. Finally, we show that NCT expression peaked 24 h after NCT cDNA transfection of wild-type and NCT-/- fibroblasts, while neprilysin expression drastically increased only after 36 h and was maximal at 48 h. This delayed effect on neprilysin expression correlates well with our demonstration of an indirect gamma-secretase-dependent modulation of neprilysin at its transcriptional level.
