![]() ![]() In AD, one of the pathological hallmarks is chronic neuro-inflammation mediated by astrocytes and microglial cells. Hence, delta-secretase plays a critical role in mediating AD pathogenesis. AEP-cleaved SET blocks the phosphatase activity of PP2A and results in Tau hyperphosphorylation and aggregation in AD 6, 7. In addition, SET also functions as a PP2A inhibitor. Previously, we reported that AEP cleaves SET that acts as a DNase inhibitor and inactivates SET, leading to DNA damage and neuronal cell death in a model of stroke 5. ![]() AEP is a lysosomal asparagine endopeptidase, and its activation is autocatalytic and requires sequential removal of N- and C-terminal peptides at different pH 4. Removal of delta-secretase from 5XFAD or Tau P301S mice ameliorates these pathological defects and rescues the cognitive functions in both animal models, suggesting that delta-secretase plays an essential role in AD onset and progression 2, 3. Delta-secretase expression levels and activity are escalated in aged mice and AD brains. We recently reported that AEP (Legumain, LGMN), newly designated as delta-secretase, cleaves both APP and Tau in an age-dependent manner 2, 3. These crucial events drive neurodegeneration and the clinical expression of dementia 1. It is known that a metabolic dysfunction of amyloid β precursor protein (APP) and abnormal Tau protein phosphorylation lead to the formation of senile plaques and neurofibrillary tangles (NFT), respectively. However, the molecular mechanisms by which aging mediates the onset and progression of AD remain unclear. The greatest known risk factor for AD is increasing age. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.Īlzheimer’s disease (AD) is characterized by the accumulation of Aβ peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein Tau. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. However, how aging contributes to an increase in delta-secretase expression and AD pathologies remains unclear. Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer’s disease (AD). ![]()
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