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>.
BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD).
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD).
Amyloid precursor protein (APP) is processed along the amyloidogenic pathway by the β-secretase, BACE1, generating β-amyloid (Aβ), or along the nonamyloidogenic pathway by α-secretase, precluding Aβ production.
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.
Aβ deposition in turn causes accumulation of BACE1 in plaque-associated dystrophic neurites, thereby potentiating progressive Aβ deposition once initiated.
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.
Focusing on the donor's sex and APOE ε4 status as nominal variables (i.e., omitting diagnosis from the stratification) revealed that increases in Aβ peptides were specific to female carriers of the ε4 allele and correlated with the proportional expression of BACE1/β-secretase and ADAM10/α-secretase in the cortex and with nicastrin (γ-secretase) expression in the hippocampus.
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.
Here, using biochemical and immunohistochemistry analyses we report that a 50% global reduction of BIN1 protein levels resulting from a single <i>Bin1</i> allele deletion in mice does not change BACE1 levels or localization <i>in vivo</i>, nor does this reduction alter the production of endogenous murine Aβ in nontransgenic mice.
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.
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.
Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain β-amyloid (Aβ) peptide's formation is a potential effective approach to treat Alzheimer's disease.