BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences <i>in vivo</i>.
The result showed that berberine significantly improved 3×Tg-AD mice's spatial learning capacity and memory retention, promoted autophagy activity identified by the enhancement of brain LC3-II, beclin-1, hVps34, and Cathepsin-D levels as well as the reduction of brain P62 and Bcl-2 levels in AD mice, facilitated reduction of Aβ and APP levels, reduced Aβ plaque deposition in the hippocampus of AD mice, and inhibited b-site APP cleavage enzyme 1 (BACE1) expression.
N-terminally truncated amyloid-β42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-β42 accumulation.
This protection appears to be due to the increased ADAM10 expression and decreased expression of both APP and BACE1, resulting in inhibition of Aβ production in the hippocampus and cortex.
Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis.
At the molecular levels, ND mitigated the increase of hippocampal beta-amyloid (Aβ<sub>42</sub>) and beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) together with down-regulation of phosphorylated tau protein.
Transcriptomic changes of BACE1-AS overexpressing and β-amyloid 1-40 treated cells were largely overlapping and indicated changes of relevant biological process such as 'cell cycle and proliferation', 'apoptosis', and 'DNA repair' as well as 'TGFβ-, TNFα-, p38-, EGFR-signalling', suggesting a potential maladaptive role of the BACE1-AS/BACE1/β-amyloid axis.
Therefore, the protective effect of acacetin on Aβ production is mediated by transcriptional regulation of BACE-1 and APP, resulting in decreased APP protein expression and BACE-1 activity.
Present study indicated that miR-29c was downregulated in sporadic AD brains, and it targeted the 3' UTR of BACE1, reduced the BACE1 expression, and downregulated the APPβ accumulation in vitro.
Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-β production and may help design potential therapeutic interventions.
Silencing gadd153 expression with siRNA alleviated the 27-OHC-induced increase in NF-κB activation, NF-κB binding to the BACE1 promoter, and subsequent increase in BACE1 transcription and Aβ production.
This study demonstrates that SNX12 can regulate the endocytosis of BACE1 through their interaction, thereby affecting β-processing of APP for Aβ production.
The level of β-site APP-cleaving enzyme 1 (BACE1) has been documented to increase in the brains of patients with Alzheimer's disease, which has resulted in elevation of β-amyloid (Aβ) peptides.
Here, we present a peptide, S1, isolated from a peptide library that selectively inhibits BACE1 hydrolytic activity by binding to the β-proteolytic site on APP and Aβ N-terminal.
We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Aβ levels and Aβ burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway.
Because the processing of APP to generate Abeta requires both gamma-secretase and BACE1, it is possible that moderate reductions of both enzymes would provide additive and significant protection against Abeta amyloidosis.
Here, we demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice.