PAR-4 Is Involved in Regulation of β-Secretase Cleavage of the Alzheimer Amyloid Precursor Protein

Xie, Jun; Guo, Qing

doi:10.1074/jbc.m411933200

Cited by 61 publications

(46 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These cellular studies therefore reinforce our assertion that the A␤42/A␤40 ratio is dependent on the substrate concentration of ␥-secretase. This finding corroborates other studies showing that up-regulation of BACE1 activity by Par4 elevates the ratio of A␤42/A␤40 (24). Our discovery illustrates that the A␤42/ A␤40 ratio is variable with ␥-secretase substrate concentration and provides critical insight into the pathogenesis of sporadic AD.…”

Section: Resultssupporting

confidence: 80%

See 1 more Smart Citation

γ-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 Ratio

Yin

Bassit

Zhu

et al. 2007

Journal of Biological Chemistry

112

View full text Add to dashboard Cite

Mutation of the amyloid precursor protein (APP), presenilin-1, or presenilin-2 results in the development of early onset autosomal dominant forms of Alzheimer disease (AD). These mutations lead to an increased A␤42/A␤40 ratio that correlates with the onset of disease. However, it remains unknown how these mutations affect ␥-secretase, a protease that generates the termini of A␤40 and A␤42. Here we have determined the reaction mechanism of ␥-secretase with wild type and three mutated APP substrates. Our findings indicate that despite the overall outcome of an increased A␤42/A␤40 ratio, these mutations each display rather distinct reactivity to ␥-secretase. Intriguingly, we found that the ratio of A␤42/A␤40 is variable with substrate concentration; increased substrate concentrations result in higher ratios of A␤42/A␤40. Moreover, we demonstrated that reduction of ␥-secretase substrate concentration by BACE1 inhibition in cells decreased the A␤42/A␤40 ratio. This study indicates that biological factors affecting targets such as BACE1 and APP, which ultimately cause an increased concentration of ␥-secretase substrate, can augment the A␤42/A␤40 ratio and may play a causative role in sporadic AD. Therefore, strategies lowering the A␤42/A␤40 ratio through partial reduction of ␥-secretase substrate production may introduce a practical therapeutic modality for treatment of AD.␥-Secretase cleaves the amyloid precursor protein (APP) to generate the C termini of ␤-amyloid (A␤) 2 peptides, generally 40 or 42 amino acids in length (A␤40 and A␤42, respectively). A␤ peptides are believed to be a major causative factor in the pathogenesis of Alzheimer disease (AD) (1). A␤42 is more prone to aggregation than A␤40 (2), and therefore biological or environmental factors that promote increased A␤42 production accelerate the pathological cascade leading to AD. Expression of A␤42, rather than A␤40, in Drosophila and mice leads to the formation of A␤ plaques (3, 4). Furthermore, mouse model studies suggest that the ratio of A␤42/A␤40, rather than total amount of A␤, correlates with the load of characteristic AD plaques in the brain (5, 6). Moreover, evidence suggests A␤40 may play a beneficial role in that it antagonizes A␤42 aggregation (5, 6). Therefore, inhibition of ␥-secretase activity that specifically generates A␤42 or reduction of the Ab42/A␤40 ratio would be an appealing strategy for treatment of AD. However, despite intensive studies on ␥-secretase, the mechanism of cleavage specificity for ␥-secretase is still unknown.APP was the first gene found to be linked with inherited AD (7). Each mutation surrounding the ␥-secretase cleavage site appears to alter the production of A␤40 and A␤42. Suzuki et al. (8) demonstrated that mutating APP at Val-46 to Phe or Ile increased the ratio of secreted A␤42 to A␤40 in transfected cells. An increased ratio of A␤42/A␤40 was also observed with other mutations (9 -11). De Jonghe et al. (9) found certain mutations enhanced the stability of the ␥-secretase substrates known as C-terminal fragm...

show abstract

Section: Resultssupporting

confidence: 80%

“…2B) and could chronically be detrimental to neuronal cells. Multiple factors have been found to regulate BACE1 expression and activity, such as Par4 (24) and HIF-1␣ (30). The role of these proteins in regulation of BACE activity in AD patients needs to be investigated.…”

Section: Resultsmentioning

confidence: 99%

γ-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 Ratio

Yin

Bassit

Zhu

et al. 2007

Journal of Biological Chemistry

112

View full text Add to dashboard Cite

show abstract

“…Many factors besides actual BACE1 levels have been proposed to regulate b-secretase activity, and may be important in further understanding the functional relationship between BACE1, and the increased V max for the enzyme detected in this study in AD. These include: heparan sulphate proteoglycans [45,46], cholesterol [47,48] lipid rafts [36,37,49], reticulon family members [50,51] and PAR-4 [52]. Changed V max in the presence of unchanged K m may reflect the loss of a non-competitive inhibitor of b-secretase activity in AD brain, and increased V max for b-secretase has been observed with BACE1 dimerisation [53].…”

Section: Discussionmentioning

confidence: 99%

Altered β‐secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain

2006

View full text Add to dashboard Cite

b-Secretase is the rate limiting enzymatic activity in the production of amyloid-b peptide, the primary component of senile plaque pathology in Alzheimer's disease (AD). This study performed the first comparative analysis of b-secretase enzyme kinetics in AD and control brain tissue. Results found V max values for b-secretase to be significantly increased, and K m values unchanged in AD temporal cortex compared to matched control temporal cortex. The increased V max in AD cases, did not correlate with levels of BACE1, and decreased BACE1 and BACE2 levels correlated with the severity of neurofibrillary pathology (I-VI), and synaptic loss in AD. These results indicate that increased V max for b-secretase is a feature of AD pathogenesis and this increase does not correlate directly with levels of BACE1, the principal b-secretase in brain.

show abstract

“…Par-4 expression is dramatically increased in hippocampal and cortical neurons in AD brain, and could be induced in cultured neurons treated with A. Overexpression of Par-4 significantly increases A42/A total ratio after trophic factor withdrawal, and this effect is blocked by co-expression of the leucine zipper domain, indicating that the modulation activity of Par-4 may depend on its interaction with other proteins [67] . Recently, the direct binding of BACE1 cytoplasmic domain with Par-4 C-terminus has been identified, and downregulation of Par-4 by siRNA could decrease the levels of -CTF and A.…”

Section: Protein Interaction Several Proteins Interacting Withmentioning

confidence: 89%

Regulation of β cleavage of amyloid precursor protein

2010

View full text Add to dashboard Cite

Alzheimer's disease ranks the first cause for senile dementia. The amyloid cascade is proposed to contribute to the pathogenesis of this disease. In this cascade, amyloid  peptide (A) is produced through a sequential cleavage of amyloid precursor protein (APP) by  and  secretases, while its cleavage by  secretase precludes A production and generates neurotrophic sAPP. Thus, enhancing  secretase activity or suppressing  and  cleavage may reduce A formation and ameliorate the pathological process of the disease. Several regulatory mechanisms of APP cleavage have been established.The present review mainly summarizes the signaling pathways pertinent to the regulation of APP  cleavage.

show abstract

PAR-4 Is Involved in Regulation of β-Secretase Cleavage of the Alzheimer Amyloid Precursor Protein

Cited by 61 publications

References 109 publications

γ-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 Ratio

γ-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 Ratio

Altered β‐secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain

Regulation of β cleavage of amyloid precursor protein

Contact Info

Product

Resources

About